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Sample records for axis regulates prostate

  1. Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis

    International Nuclear Information System (INIS)

    Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated. PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin α and β subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin α and β subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination. Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer

  2. SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis

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    Uygur Berna

    2011-11-01

    Full Text Available Abstract Background SLUG is a zinc-finger transcription factor of the Snail/Slug zinc-finger family that plays a role in migration and invasion of tumor cells. Mechanisms by which SLUG promotes migration and invasion in prostate cancers remain elusive. Methods Expression level of CXCR4 and CXCL12 was examined by Western blot, RT-PCR, and qPCR analyses. Forced expression of SLUG was mediated by retroviruses, and SLUG and CXCL12 was downregulated by shRNAs-expressing lentiviruses. Migration and invasion of prostate cancer were measured by scratch-wound assay and invasion assay, respectively. Research We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. We showed that CXCL12 is required for SLUG-mediated MMP9 expression in prostate cancer cells. Moreover, we found that migration and invasion of prostate cancer cells was increased by ectopic expression of SLUG and decreased by SLUG knockdown. Notably, knockdown of CXCL12 by shRNA impaired SLUG-mediated migration and invasion in prostate cancer cells. Lastly, our data suggest that CXCL12 and SLUG regulate migration and invasion of prostate cancer cells independent of cell growth. Conclusion We provide the first compelling evidence that upregulation of autocrine CXCL12 is a major mechanism underlying SLUG-mediated migration and invasion of prostate cancer cells. Our findings suggest that CXCL12 is a therapeutic target for prostate cancer metastasis.

  3. Neuroactive steroids and stress axis regulation: Pregnancy and beyond.

    Science.gov (United States)

    Brunton, Paula J

    2016-06-01

    The hypothalamo-pituitary-adrenal (HPA) axis plays a critical role in regulating responses to stress and long term dysregulation of the HPA axis is associated with higher rates of mood disorders. There are circumstances where the HPA axis is more or less responsive to stress. For example, during late pregnancy ACTH and corticosterone responses to stress are markedly suppressed, whereas in offspring born to mothers that experienced repeated stress during pregnancy, the HPA axis is hyper-responsive to stress. Neuroactive steroids such as allopregnanolone, tetrahydrodeoxycorticosterone (THDOC) and androstanediol can modulate HPA axis activity and concentrations of some neuroactive steroids in the brain are altered during pregnancy and following stress. Thus, here altered neurosteroidogenesis is proposed as a mechanism that could underpin the dynamic changes in HPA axis regulation typically observed in late pregnant and in prenatally stressed individuals. In support of this hypothesis, evidence in rats demonstrates that elevated levels of allopregnanolone in pregnancy induce a central inhibitory opioid mechanism that serves to minimize stress-induced HPA axis activity. Conversely, in prenatally stressed rodents, where HPA axis stress responses are enhanced, evidence indicates the capacity of the brain for neurosteroidogenesis is reduced. Understanding the mechanisms involved in adaptations in HPA axis regulation may provide insights for manipulating stress sensitivity and for developing therapies for stress-related disorders in humans. PMID:26259885

  4. Genes regulated by androgen in the rat ventral prostate

    OpenAIRE

    Wang, Zhou; Tufts, Rachel; Haleem, Riffat; Cai, Xiaoyan

    1997-01-01

    Genes that are regulated by androgen in the prostate were studied in the rat. Four of the less than 10 genes that are down-regulated by androgen in the ventral prostate of a 7-day castrated rat were identified; their mRNAs decayed with identical kinetics. Twenty-five of the estimated 56 genes that are up-regulated by androgen in the castrated prostate have been isolated. The up-regulated genes fall into two kinetic types. Early genes are significantly up-regulated by 6.5 hr whereas the delaye...

  5. Regulation of surfactant protein D in the rodent prostate

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    Maldonado Cristina A

    2007-11-01

    Full Text Available Abstract Background Surfactant protein D (SP-D is an innate immune protein that is present in mucosal lined surfaces throughout the human body, including the male reproductive tract. In the present study, we characterized the regulation of SP-D expression in the mouse and rat prostate. Methods Real time reverse transcriptase polymerase chain reaction (RT-PCR and immunostaining were used to characterize SP-D mRNA and protein in the mouse male reproductive tract. In order to evaluate the effects of testosterone on SP-D gene expression, we measured SP-D mRNA levels via real time RT-PCR in prostates from sham-castrated mice and castrated mice. In addition, we used a rat prostatitis model in which Escherichia coli was injected into the prostate in vivo to determine if infection influences SP-D protein levels in the prostate. Results We found that SP-D mRNA and protein are present throughout the mouse male reproductive tract, including in the prostate. We determined that castration increases prostate SP-D mRNA levels (~7 fold when compared to levels in sham-castrated animals. Finally, we demonstrated that infection in the prostate results in a significant increase in SP-D content 24 and 48 hours post-infection. Conclusion Our results suggest that infection and androgens regulate SP-D in the prostate.

  6. Three-axis MR-conditional robot for high-intensity focused ultrasound for treating prostate diseases transrectally

    OpenAIRE

    Yiallouras, Christos; Ioannides, Kleanthis; Dadakova, Tetiana; Pavlina, Matt; Bock, Michael; Damianou, Christakis

    2015-01-01

    Background A prototype magnetic resonance image (MRI)-conditional robot was developed for navigating a high-intensity focused ultrasound (HIFU) system in order to treat prostate cancer transrectally. Materials and methods The developed robotic device utilizes three PC-controlled axes: a linear axis for motion along the rectum, an angular axis for rotation in the rectum, and a linear axis to lift the robot up and down. Experiments with the system were performed in a 1.5-T MRI system using gel ...

  7. The diet-microbiota-metabolite axis regulates the host physiology.

    Science.gov (United States)

    Yamada, Takahiro; Takahashi, Daisuke; Hase, Koji

    2016-07-01

    The intestinal microbiota has been implicated in a wide range of diseases, including inflammatory bowel disease, obesity and cancer. Food ingredients are considered a major determinant of gut microbial composition, as exemplified by high-fat diet-induced dysbiosis that can affect host physiology. Accumulating studies show that microbial metabolites are key regulators of the intestinal epithelial barrier and gut immunity. In particular, short-chain fatty acids produced by bacterial fermentation of indigestible polysaccharides have profound impacts on host physiology beyond the gut. In this review, we describe the influences of the diet-microbiota-metabolite axis on host physiology, and especially on the immune and metabolic systems. PMID:26970281

  8. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

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    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  9. TMPRSS2/ERG Promotes Epithelial to Mesenchymal Transition through the ZEB1/ZEB2 Axis in a Prostate Cancer Model

    OpenAIRE

    Leshem, Orit; Madar, Shalom; Kogan-Sakin, Ira; Kamer, Iris; Goldstein, Ido; Brosh, Ran; COHEN, YEHUDIT; Jacob-Hirsch, Jasmine; Ehrlich, Marcelo; Ben-Sasson, Shmuel; Goldfinger, Naomi; Loewenthal, Ron; Gazit, Ephraim; Rotter, Varda; Berger, Raanan

    2011-01-01

    Prostate cancer is the most common non-dermatologic malignancy in men in the Western world. Recently, a frequent chromosomal aberration fusing androgen regulated TMPRSS2 promoter and the ERG gene (TMPRSS2/ERG) was discovered in prostate cancer. Several studies demonstrated cooperation between TMPRSS2/ERG and other defective pathways in cancer progression. However, the unveiling of more specific pathways in which TMPRSS2/ERG takes part, requires further investigation. Using immortalized prosta...

  10. Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer

    Science.gov (United States)

    Antonarakis, Emmanuel S.

    2016-01-01

    While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient's response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms. PMID:26902623

  11. Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

    OpenAIRE

    Roman, Kenny; Done, Joseph D.; Schaeffer, Anthony J.; Murphy, Stephen F.; Thumbikat, Praveen

    2014-01-01

    Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined ...

  12. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

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    Mingzhe Liu

    2016-01-01

    Full Text Available Hydrogen sulfide (H2S was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer.

  13. Periostin is up-regulated in high grade and high stage prostate cancer

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    Schraml Peter

    2010-06-01

    Full Text Available Abstract Background Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. Methods Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93 and a test cohort (n = 325. Metastatic prostate cancers (n = 20, hormone refractory prostate cancers (n = 19 and benign prostatic tissues (n = 38 were also analyzed. Results In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0% of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%. Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p Conclusions Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.

  14. An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension

    Science.gov (United States)

    Anderson, Matthew J.; Schimmang, Thomas; Lewandoski, Mark

    2016-01-01

    During vertebrate axis extension, adjacent tissue layers undergo profound morphological changes: within the neuroepithelium, neural tube closure and neural crest formation are occurring, while within the paraxial mesoderm somites are segmenting from the presomitic mesoderm (PSM). Little is known about the signals between these tissues that regulate their coordinated morphogenesis. Here, we analyze the posterior axis truncation of mouse Fgf3 null homozygotes and demonstrate that the earliest role of PSM-derived FGF3 is to regulate BMP signals in the adjacent neuroepithelium. FGF3 loss causes elevated BMP signals leading to increased neuroepithelium proliferation, delay in neural tube closure and premature neural crest specification. We demonstrate that elevated BMP4 depletes PSM progenitors in vitro, phenocopying the Fgf3 mutant, suggesting that excessive BMP signals cause the Fgf3 axis defect. To test this in vivo we increased BMP signaling in Fgf3 mutants by removing one copy of Noggin, which encodes a BMP antagonist. In such mutants, all parameters of the Fgf3 phenotype were exacerbated: neural tube closure delay, premature neural crest specification, and premature axis termination. Conversely, genetically decreasing BMP signaling in Fgf3 mutants, via loss of BMP receptor activity, alleviates morphological defects. Aberrant apoptosis is observed in the Fgf3 mutant tailbud. However, we demonstrate that cell death does not cause the Fgf3 phenotype: blocking apoptosis via deletion of pro-apoptotic genes surprisingly increases all Fgf3 defects including causing spina bifida. We demonstrate that this counterintuitive consequence of blocking apoptosis is caused by the increased survival of BMP-producing cells in the neuroepithelium. Thus, we show that FGF3 in the caudal vertebrate embryo regulates BMP signaling in the neuroepithelium, which in turn regulates neural tube closure, neural crest specification and axis termination. Uncovering this FGF3-BMP signaling axis is

  15. An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension.

    Directory of Open Access Journals (Sweden)

    Matthew J Anderson

    2016-05-01

    Full Text Available During vertebrate axis extension, adjacent tissue layers undergo profound morphological changes: within the neuroepithelium, neural tube closure and neural crest formation are occurring, while within the paraxial mesoderm somites are segmenting from the presomitic mesoderm (PSM. Little is known about the signals between these tissues that regulate their coordinated morphogenesis. Here, we analyze the posterior axis truncation of mouse Fgf3 null homozygotes and demonstrate that the earliest role of PSM-derived FGF3 is to regulate BMP signals in the adjacent neuroepithelium. FGF3 loss causes elevated BMP signals leading to increased neuroepithelium proliferation, delay in neural tube closure and premature neural crest specification. We demonstrate that elevated BMP4 depletes PSM progenitors in vitro, phenocopying the Fgf3 mutant, suggesting that excessive BMP signals cause the Fgf3 axis defect. To test this in vivo we increased BMP signaling in Fgf3 mutants by removing one copy of Noggin, which encodes a BMP antagonist. In such mutants, all parameters of the Fgf3 phenotype were exacerbated: neural tube closure delay, premature neural crest specification, and premature axis termination. Conversely, genetically decreasing BMP signaling in Fgf3 mutants, via loss of BMP receptor activity, alleviates morphological defects. Aberrant apoptosis is observed in the Fgf3 mutant tailbud. However, we demonstrate that cell death does not cause the Fgf3 phenotype: blocking apoptosis via deletion of pro-apoptotic genes surprisingly increases all Fgf3 defects including causing spina bifida. We demonstrate that this counterintuitive consequence of blocking apoptosis is caused by the increased survival of BMP-producing cells in the neuroepithelium. Thus, we show that FGF3 in the caudal vertebrate embryo regulates BMP signaling in the neuroepithelium, which in turn regulates neural tube closure, neural crest specification and axis termination. Uncovering this FGF3

  16. LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth and invasion

    OpenAIRE

    Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J.; Ferrari, Anna; Lee, Peng

    2009-01-01

    A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LE...

  17. STAT3 regulated ARF expression suppresses prostate cancer metastasis

    Science.gov (United States)

    Pencik, Jan; Schlederer, Michaela; Gruber, Wolfgang; Unger, Christine; Walker, Steven M.; Chalaris, Athena; Marié, Isabelle J.; Hassler, Melanie R.; Javaheri, Tahereh; Aksoy, Osman; Blayney, Jaine K.; Prutsch, Nicole; Skucha, Anna; Herac, Merima; Krämer, Oliver H.; Mazal, Peter; Grebien, Florian; Egger, Gerda; Poli, Valeria; Mikulits, Wolfgang; Eferl, Robert; Esterbauer, Harald; Kennedy, Richard; Fend, Falko; Scharpf, Marcus; Braun, Martin; Perner, Sven; Levy, David E.; Malcolm, Tim; Turner, Suzanne D.; Haitel, Andrea; Susani, Martin; Moazzami, Ali; Rose-John, Stefan; Aberger, Fritz; Merkel, Olaf; Moriggl, Richard; Culig, Zoran; Dolznig, Helmut; Kenner, Lukas

    2015-01-01

    Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition. PMID:26198641

  18. Periostin is up-regulated in high grade and high stage prostate cancer

    International Nuclear Information System (INIS)

    Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed. In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05). Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer

  19. Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Setya Hemani

    2008-07-01

    Full Text Available Abstract Background Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. Results We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. Conclusion This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect.

  20. Stress and serial adult metamorphosis: multiple roles for the stress axis in socially regulated sex change

    OpenAIRE

    Solomon-Lane, Tessa K.; Crespi, Erica J.; Matthew Scott Grober

    2013-01-01

    Socially regulated sex change in teleost fishes is a striking example of social status information regulating biological function in the service of reproductive success. The establishment of social dominance in sex changing species is translated into a cascade of changes in behavior, physiology, neuroendocrine function, and morphology that transforms a female into a male, or vice versa. The hypothalamic-pituitary-interrenal axis (HPI, homologous to HP-adrenal axis in mammals and birds) has ...

  1. Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status

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    Naitao Wang

    2016-05-01

    Full Text Available Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3 was upregulated in a large subset of benign prostatic hyperplasia (BPH tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH.

  2. TCTP is an androgen-regulated gene implicated in prostate cancer.

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    Mari Kaarbø

    Full Text Available TCTP has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. In addition to these intracellular functions, TCTP has extracellular functions and plays an important role in immune cells. TCTP expression was previously shown to be deregulated in prostate cancer, but its function in prostate cancer cells is largely unknown. Here we show that TCTP expression is regulated by androgens in LNCaP prostate cancer cells in vitro as well as human prostate cancer xenografts in vivo. Knockdown of TCTP reduced colony formation and increased apoptosis in LNCaP cells, implicating it as an important factor for prostate cancer cell growth. Global gene expression profiling in TCTP knockdown LNCaP cells showed that several interferon regulated genes are regulated by TCTP, suggesting that it may have a role in regulating immune function in prostate cancer. In addition, recombinant TCTP treatment increased colony formation in LNCaP cells suggesting that secreted TCTP may function as a proliferative factor in prostate cancer. These results suggest that TCTP may have a role in prostate cancer development.

  3. Liver-gut axis in the regulation of iron homeostasis

    Institute of Scientific and Technical Information of China (English)

    Deepak Darshan; Gregory J Anderson

    2007-01-01

    The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron,the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.

  4. Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells

    OpenAIRE

    Chen, Mengqian; Tanner, Matthew; Levine, Alice C.; Levina, Elina; Ohouo, Patrice; Buttyan, Ralph

    2009-01-01

    Hedgehog signaling is thought to play a role in several human cancers including prostate cancer. Although prostate cancer cells express many of the gene products involved in hedgehog signaling, these cells are refractory to the canonical signaling effects of exogenous hedgehog ligands or to activated Smoothened, the hedgehog-regulated mediator of Gli transcriptional activation. Here, we show that the expression of hedgehog ligands and some hedgehog target genes are regulated by androgen in th...

  5. Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells

    OpenAIRE

    Singh, Prashant K.; Doig, Craig L.; Dhiman, Vineet K; Turner, Bryan M.; Smiraglia, Dominic J; Campbell, Moray J.

    2012-01-01

    The current study aimed to examine the gene specific mechanisms by which the actions of the vitamin D receptor (VDR) are distorted in prostate cancer. Transcriptional responses toward the VDR ligand, 1α,25(OH)2D3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1α,25(OH)2D3-recalcitrant prostate cancer cells (PC-3). Time resolved transcriptional studies for two VDR target genes revealed selective attenuation and repression of VDR transcriptional responses...

  6. ERβ regulation of NF-kB activation in prostate cancer is mediated by HIF-1.

    Science.gov (United States)

    Mak, Paul; Li, Jiarong; Samanta, Sanjoy; Mercurio, Arthur M

    2015-11-24

    We examined the regulation of NF-κB in prostate cancer by estrogen receptor β (ERβ) based on the inverse correlation between p65 and ERβ expression that exists in prostate carcinomas and reports that ERβ can inhibit NF-κB activation, although the mechanism is not known. We demonstrate that ERβ functions as a gate-keeper for NF-κB p65 signaling by repressing its expression and nuclear translocation. ERβ regulation of NF-κB signaling is mediated by HIF-1. Loss of ERβ or hypoxia stabilizes HIF-1α, which we found to be a direct driver of IKKβ transcription through a hypoxia response element present in the promoter of the IKKβ gene. The increase of IKKβ expression in ERβ-ablated cells correlates with an increase in phospho-IκBα and concomitant p65 nuclear translocation. An inverse correlation between the expression of ERβ and IKKβ/p65 was also observed in the prostates of ERβ knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ERβ prevents NF-κB activation and raise the exciting possibility that loss of ERβ expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer. PMID:26450901

  7. Primary cilia function regulates the length of the embryonic trunk axis and urogenital field in mice

    DEFF Research Database (Denmark)

    Wainwright, Elanor N.; Svingen, Terje; Ting Ng, Ee;

    2014-01-01

    The issues of whether and how some organs coordinate their size and shape with the blueprint of the embryo axis, while others appear to regulate their morphogenesis autonomously, remain poorly understood. Mutations in Ift144, encoding a component of the trafficking machinery of primary cilia...

  8. The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance.

    Science.gov (United States)

    Nieuwenhuizen, Arie G; Rutters, Femke

    2008-05-23

    Human (visceral) obesity is associated with alterations hypothalamus-pituitary-adrenal (HPA) axis functioning. It is however not completely clear whether the HPA axis is causally or co-incidentally related to (visceral) obesity. This review summarizes supporting data of an involvement of the HPA axis in the development of (visceral) obesity. First, several DNA polymorphisms related to HPA axis functioning are correlated to the development of obesity. Second, chronic elevation of circulatory glucocorticoid concentrations, as in Cushing's disease, results in increased abdominal adiposity. Third, (visceral) obesity is associated with a diminished capacity of cortisol to suppress its own secretion. HPA axis functioning might affect energy balance through affecting energy intake. Both CRH and cortisol influence physiological, central mechanisms involved in the regulation of food intake. Still, general activation of the HPA axis has shown to have inconsistent effects on food intake in humans. This inconsistency may partially be explained by gender differences, individual differences in the functioning of the HPA axis, as well as differences in attitude towards eating. In particular, women with high scores on dietary restraint are prone to stress-induced hyperphagia. Dietary restraint scores, in turn, are positively correlated to basal and dexamethasone-suppressed cortisol levels, indicating a complex dual relationship between stress, HPA axis functioning, attitude towards eating and the risk for stress-induced hyperphagia. In the Western society, with chronically high ambient levels of stress and the availability of high caloric foods, this relationship may imply a risk for the development of (visceral) obesity and the metabolic syndrome. PMID:18275977

  9. Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: Regulation of MMP 9 by PDEF

    Directory of Open Access Journals (Sweden)

    Meacham Randall B

    2010-06-01

    and increased MMP9 expression during the transition to aggressive prostate cancer. Conclusions These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, and that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP9 expression in clinical samples of prostate cancer. Based on these exciting results, we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer.

  10. Neuromedins U and S involvement in the regulation of the hypothalamo - pituitary - adrenal axis.

    Directory of Open Access Journals (Sweden)

    Ludwik K. Malendowicz

    2012-12-01

    Full Text Available Abstract: We reviewed neuromedin U (NMU and neuromedin S (NMS involvement in the regulation of the hypothalamo - pituitary - adrenal (HPA axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expressed in the HPA axis and progress in molecular biology techniques provided new information on their actions within this system. Several lines of evidence suggest that within the HPA axis NMU and NMS act at both hypothalamic and adrenal levels. Moreover, new data suggest that NMU and NMS are involved in central and peripheral control of the stress response.

  11. hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer

    Directory of Open Access Journals (Sweden)

    Kajdacsy-Balla André

    2005-09-01

    Full Text Available Abstract Background The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1 as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. Results hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands. In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN. These changes occur early in malignancy and are sustained during its progression in the peripheral zone. hZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation

  12. Neuromedins U and S involvement in the regulation of the hypothalamo - pituitary - adrenal axis.

    OpenAIRE

    Ludwik K Malendowicz; Agnieszka eZiolkowska; Marcin eRucinski

    2012-01-01

    Abstract: We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo - pituitary - adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are...

  13. Neuromedins U and S involvement in the regulation of the hypothalamo–pituitary–adrenal axis

    OpenAIRE

    Ludwik K Malendowicz; Ziolkowska, Agnieszka; Rucinski, Marcin

    2012-01-01

    We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo–pituitary–adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expresse...

  14. The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload

    OpenAIRE

    Masataka Ikeda; Tomomi Ide; Takeo Fujino; Yuka Matsuo; Shinobu Arai; Keita Saku; Takamori Kakino; Yasuhiro Oga; Akiko Nishizaki; Kenji Sunagawa

    2015-01-01

    The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-depende...

  15. Differential environmental regulation of neurogenesis along the septo-temporal axis of the hippocampus.

    Science.gov (United States)

    Tanti, Arnaud; Rainer, Quentin; Minier, Frederic; Surget, Alexandre; Belzung, Catherine

    2012-09-01

    The hippocampus is involved in both cognitive and emotional processing; these different functions are topographically distributed along its septo-temporal axis, the dorsal (septal) hippocampus being preferentially involved in cognitive processes such as learning and memory while the ventral (temporal) hippocampus participates in emotional regulation and anxiety-related behaviors. Newborn hippocampal neurons become functionally integrated into hippocampal networks and are likely to contribute to hippocampal functions, but whether their regulation and function are homogenous throughout this axis is not clear. Here we investigate changes in cell proliferation and neurogenesis along the septo-temporal axis of the hippocampus induced by the Unpredictable Chronic Mild Stress model of depression (UCMS), chronic fluoxetine treatment and enriched environment. Mice were either subjected to UCMS, standard housing or enriched environment. Stress-exposed mice were treated daily with fluoxetine (10 mg/kg) or vehicle. Effects of UCMS regimen, fluoxetine treatment and enrichment were assessed by physical measures and behavioral testing. Quantitative changes in cell proliferation and neurogenesis were assessed by immunohistochemistry using BrdU labeling. Results indicate that UCMS decreased cell proliferation and neurogenesis preferentially in the ventral hippocampus, an effect that was reversed by fluoxetine treatment. Environmental enrichment on the other hand increased cell proliferation in both divisions but promoted neurogenesis only in the dorsal hippocampus. These results indicate that environmental factors can differentially regulate neurogenesis in a region-specific manner. This may possibly underlie heterogeneous function of newborn neurons along the septo-temporal axis of the hippocampus and have functional significance as to their implication in stress related disorders and memory processes. PMID:22561281

  16. Snail transcription factor negatively regulates maspin tumor suppressor in human prostate cancer cells

    International Nuclear Information System (INIS)

    Maspin, a putative tumor suppressor that is down-regulated in breast and prostate cancer, has been associated with decreased cell motility. Snail transcription factor is a zinc finger protein that is increased in breast cancer and is associated with increased tumor motility and invasion by induction of epithelial-mesenchymal transition (EMT). We investigated the molecular mechanisms by which Snail increases tumor motility and invasion utilizing prostate cancer cells. Expression levels were analyzed by RT-PCR and western blot analyses. Cell motility and invasion assays were performed, while Snail regulation and binding to maspin promoter was analyzed by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Snail protein expression was higher in different prostate cancer cells lines as compared to normal prostate epithelial cells, which correlated inversely with maspin expression. Snail overexpression in 22Rv1 prostate cancer cells inhibited maspin expression and led to increased migration and invasion. Knockdown of Snail in DU145 and C4-2 cancer cells resulted in up-regulation of maspin expression, concomitant with decreased migration. Transfection of Snail into 22Rv1 or LNCaP cells inhibited maspin promoter activity, while stable knockdown of Snail in C4-2 cells increased promoter activity. ChIP analysis showed that Snail is recruited to the maspin promoter in 22Rv1 cells. Overall, this is the first report showing that Snail can negatively regulate maspin expression by directly repressing maspin promoter activity, leading to increased cell migration and invasion. Therefore, therapeutic targeting of Snail may be useful to re-induce expression of maspin tumor suppressor and prevent prostate cancer tumor progression

  17. The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells.

    Science.gov (United States)

    Olokpa, Emuejevoke; Bolden, Adrienne; Stewart, LaMonica V

    2016-12-01

    The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells. qRT-PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARγ mRNA and protein within the castration-resistant, AR-positive C4-2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARγ levels. In addition, siRNA mediated knockdown of AR increased PPARγ protein levels and ligand-induced PPARγ transcriptional activity within the C4-2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARγ and prevented the DHT-mediated suppression of PPARγ. These data suggest that AR normally functions to suppress PPARγ expression within AR-positive prostate cancer cells. To determine whether increases in AR protein would influence PPARγ expression and activity, we used lipofectamine-based transfections to overexpress AR within the AR-null PC-3 cells. The addition of AR to PC-3 cells did not significantly alter PPARγ protein levels. However, the ability of the PPARγ ligand rosiglitazone to induce activation of a PPARγ-driven luciferase reporter and induce expression of FABP4 was suppressed in AR-positive PC-3 cells. Together, these data indicate AR serves as a key modulator of PPARγ expression and function within prostate tumors. J. Cell. Physiol. 231: 2664-2672, 2016. © 2016 Wiley Periodicals, Inc. PMID:26945682

  18. Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer

    Science.gov (United States)

    Luo, Wei; Karpf, Adam R.; Deeb, Kristin K.; Muindi, Josephia R.; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.

    2010-01-01

    Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. ChIP-qPCR reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of VDR to the CYP24A1 promoter. RT-PCR analysis of paired human prostate samples reveals that CYP24A1 expression is down-regulated in prostate malignant lesions compared to adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared to matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications. PMID:20587525

  19. Regulation of prostate cancer progression by the tumor microenvironment.

    Science.gov (United States)

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  20. The metabolic co-regulator PGC1α suppresses prostate cancer metastasis.

    Science.gov (United States)

    Torrano, Veronica; Valcarcel-Jimenez, Lorea; Cortazar, Ana Rosa; Liu, Xiaojing; Urosevic, Jelena; Castillo-Martin, Mireia; Fernández-Ruiz, Sonia; Morciano, Giampaolo; Caro-Maldonado, Alfredo; Guiu, Marc; Zúñiga-García, Patricia; Graupera, Mariona; Bellmunt, Anna; Pandya, Pahini; Lorente, Mar; Martín-Martín, Natalia; David Sutherland, James; Sanchez-Mosquera, Pilar; Bozal-Basterra, Laura; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Berenguer, Antonio; Embade, Nieves; Ugalde-Olano, Aitziber; Lacasa-Viscasillas, Isabel; Loizaga-Iriarte, Ana; Unda-Urzaiz, Miguel; Schultz, Nikolaus; Aransay, Ana Maria; Sanz-Moreno, Victoria; Barrio, Rosa; Velasco, Guillermo; Pinton, Paolo; Cordon-Cardo, Carlos; Locasale, Jason W; Gomis, Roger R; Carracedo, Arkaitz

    2016-06-01

    Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment. PMID:27214280

  1. Zinc Finger 280B Regulates sGCα1 and p53 in Prostate Cancer Cells

    OpenAIRE

    Gao, Shuai; Hsieh, Chen-Lin; Zhou, Jun; Shemshedini, Lirim

    2013-01-01

    The Zinc Finger (ZNF) 280B protein was identified as an unexpected target of an shRNA designed for sGCα1. Further analysis showed that these two proteins are connected in another way, with 280B up-regulation of sGCα1 expression. Knock-down and over-expression experiments showed that 280B serves pro-growth and pro-survival functions in prostate cancer. Surprisingly however, these pro-cancer functions of 280B are not mediated by sGCα1, which itself has similar functions in prostate cancer, but ...

  2. Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

    2014-04-25

    Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

  3. Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

    International Nuclear Information System (INIS)

    Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex

  4. N-myc Downstream Regulated Gene 1 (NDRG1 Is Fused to ERG in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Dorothee Pflueger

    2009-08-01

    Full Text Available A step toward the molecular classification of prostate cancer was the discovery of recurrent erythroblast transformation. specific rearrangements, most commonly fusing the androgen-regulated TMPRSS2 promoter to ERG. The TMPRSS2-ERG fusion is observed in around 90% of tumors that overexpress the oncogene ERG. The goal of the current study was to complete the characterization of these ERG-overexpressing prostate cancers. Using fluorescence in situ hybridization and reverse transcription.polymerase chain reaction assays, we screened 101 prostate cancers, identifying 34 cases (34% with the TMPRSS2-ERG fusion. Seven cases demonstrated ERG rearrangement by fluorescence in situ hybridization without the presence of TMPRSS2-ERG fusion messenger RNA transcripts. Screening for known 5' partners, we determined that three cases harbored the SLC45A3-ERG fusion. To discover novel 5' partners in these ERG-overexpressing and ERG-rearranged cases, we used paired-end RNA sequencing. We first confirmed the utility of this approach by identifying the TMPRSS2-ERG fusion in a known positive prostate cancer case and then discovered a novel fusion involving the androgen-inducible tumor suppressor, NDRG1 (N-myc downstream regulated gene 1, and ERG in two cases. Unlike TMPRSS2-ERG and SCL45A3-ERG fusions, the NDRG1-ERG fusion is predicted to encode a chimeric protein. Like TMPRSS2, SCL45A3 and NDRG1 are inducible not only by androgen but also by estrogen. This study demonstrates that most ERG-overexpressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions. Broader implications of this study support the use of RNA sequencing to discover novel cancer translocations.

  5. Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Tomomi; Shimada, Keiji [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan); Tatsumi, Yoshihiro [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan); Department of Urology, Nara Medical University School of Medicine, Nara (Japan); Fujimoto, Kiyohide [Department of Urology, Nara Medical University School of Medicine, Nara (Japan); Konishi, Noboru, E-mail: nkonishi@naramed-u.ac.jp [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan)

    2015-01-02

    Highlights: • Syndecan-1 is highly expressed in androgen independent prostate cancer cells, PC3. • Syndecan-1 regulates the expression of miR-126 and -149 in prostate cancer cells. • MiR-126 and 149 control cell growth via p21 induction and senescence mechanism. • MiR-126 and 149 promote cell proliferation by suppressing SOX2, NANOG, and Oct4. - Abstract: MicroRNAs (miRNAs) are short (19–24 nt), low molecular weight RNAs that play important roles in the regulation of target genes associated with cell proliferation, differentiation, and development, by binding to the 3′-untranslated region of the target mRNAs. In this study, we examined the expression of miRNA-126 (miR-126) and miR-149 in prostate cancer, and investigated the molecular mechanisms by which they affect syndecan-1 in prostate cancer. Functional analysis of miR-126 and miR-149 was conducted in the prostate cancer cell lines, PC3, Du145, and LNCaP. The expression levels of SOX2, NANOG, Oct4, miR-126 and miR-149 were evaluated by quantitative RT-PCR. After silencing syndecan-1, miR-126, and/or miR-149 in the PC3 cells, cell proliferation, senescence, and p21 induction were assessed using the MTS assay, senescence-associated β-galactosidase (SA-β-Gal) assay, and immunocytochemistry, respectively. Compared to the Du145 and LNCaP cells, PC3 cells exhibited higher expression of syndecan-1. When syndecan-1 was silenced, the PC3 cells showed reduced expression of miR-126 and miR-149 most effectively. Suppression of miR-126 and/or miR-149 significantly inhibited cell growth via p21 induction and subsequently, induced senescence. The mRNA expression levels of SOX2, NANOG, and Oct4 were significantly increased in response to the silencing of miR-126 and/or miR-149. Our results suggest that miR-126 and miR-149 are associated with the expression of syndecan-1 in prostate cancer cells. These miRNAs promote cell proliferation by suppressing SOX2, NANOG, and Oct4. The regulation of these factors by mi

  6. Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer

    International Nuclear Information System (INIS)

    Highlights: • Syndecan-1 is highly expressed in androgen independent prostate cancer cells, PC3. • Syndecan-1 regulates the expression of miR-126 and -149 in prostate cancer cells. • MiR-126 and 149 control cell growth via p21 induction and senescence mechanism. • MiR-126 and 149 promote cell proliferation by suppressing SOX2, NANOG, and Oct4. - Abstract: MicroRNAs (miRNAs) are short (19–24 nt), low molecular weight RNAs that play important roles in the regulation of target genes associated with cell proliferation, differentiation, and development, by binding to the 3′-untranslated region of the target mRNAs. In this study, we examined the expression of miRNA-126 (miR-126) and miR-149 in prostate cancer, and investigated the molecular mechanisms by which they affect syndecan-1 in prostate cancer. Functional analysis of miR-126 and miR-149 was conducted in the prostate cancer cell lines, PC3, Du145, and LNCaP. The expression levels of SOX2, NANOG, Oct4, miR-126 and miR-149 were evaluated by quantitative RT-PCR. After silencing syndecan-1, miR-126, and/or miR-149 in the PC3 cells, cell proliferation, senescence, and p21 induction were assessed using the MTS assay, senescence-associated β-galactosidase (SA-β-Gal) assay, and immunocytochemistry, respectively. Compared to the Du145 and LNCaP cells, PC3 cells exhibited higher expression of syndecan-1. When syndecan-1 was silenced, the PC3 cells showed reduced expression of miR-126 and miR-149 most effectively. Suppression of miR-126 and/or miR-149 significantly inhibited cell growth via p21 induction and subsequently, induced senescence. The mRNA expression levels of SOX2, NANOG, and Oct4 were significantly increased in response to the silencing of miR-126 and/or miR-149. Our results suggest that miR-126 and miR-149 are associated with the expression of syndecan-1 in prostate cancer cells. These miRNAs promote cell proliferation by suppressing SOX2, NANOG, and Oct4. The regulation of these factors by mi

  7. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis

    Science.gov (United States)

    Oury, Franck; Ferron, Mathieu; Huizhen, Wang; Confavreux, Cyrille; Xu, Lin; Lacombe, Julie; Srinivas, Prashanth; Chamouni, Alexandre; Lugani, Francesca; Lejeune, Herve; Kumar, T. Rajendra; Plotton, Ingrid; Karsenty, Gerard

    2013-01-01

    The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin’s reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans. PMID:23728177

  8. A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination

    Science.gov (United States)

    Ahronian, Leanne G.; Zhu, Lihua Julie; Chen, Ya-Wen; Chu, Hsiao-Chien; Klimstra, David S.; Lewis, Brian C.

    2016-01-01

    The presence of invasion into the extra-hepatic portion of the portal vein or the development of distant metastases renders hepatocellular carcinoma (HCC) patients ineligible for the only potential curative options for this malignancy - tumor resection or organ transplantation. Gene expression profiling of murine HCC cell lines identified KLF6 as a potential regulator of HCC cell migration. KLF6 knockdown increases cell migration, consistent with the correlation between decreased KLF6 mRNA levels and the presence of vascular invasion in human HCC. Concordantly, single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs, and decreased survival, indicating that KLF6 suppresses both HCC development and metastasis. By combining gene expression profiling and chromatin immunoprecipitation coupled to deep sequencing, we identified novel transcriptional targets of KLF6 in HCC cells including VAV3, a known activator of the RAC1 small GTPase. Indeed, RAC1 activity is increased in KLF6 knockdown cells in a VAV3-dependent manner, and knockdown of either RAC1 or VAV3 impairs HCC cell migration. Together, our data demonstrate a novel function for KLF6 in constraining HCC dissemination through the regulation of a VAV3-RAC1 signaling axis. PMID:26876204

  9. Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent.

    Science.gov (United States)

    Purushottamachar, Puranik; Khandelwal, Aakanksha; Vasaitis, Tadas S; Bruno, Robert D; Gediya, Lalji K; Njar, Vincent C O

    2008-04-01

    The search for novel androgen receptor (AR) down-regulating agents by catalyst HipHop pharmacophore modeling led to the discovery of some lead molecules. Unexpectedly, the effect of these leads on human prostate cancer LNCaP cell viability did not correlate with the ability of the compounds to cause down-regulation of AR protein expression. Through rational synthetic optimization of the lead compound (BTB01434), we have discovered a series of novel substituted diaryl molecules as potent anti-prostate cancer agents. Some compounds (1-6) were shown to be extremely potent inhibitors of LNCaP cell viability with GI(50) values in the nanomolar range (1.45-83 nM). The most potent compound (4-methylphenyl)[(4-methylphenyl)sulfonyl]amine (5) with a GI(50) value of 1.45 nM is 27,000 times more potent than our lead compound BTB01434 (GI(50)=39.8 microM). In addition, some of the compounds exhibited modest anti-androgenic activities and one was also a potent inhibitor (GI(50)=850 nM) of PC-3 (AR-null) cell growth. A clear structure-activity relationship (SAR) has been established for activity against LNCaP cells, where potent molecules possess two substituted/unsubstituted aromatic rings connected through a sulfonamide linker. These novel compounds are strong candidates for development for the treatment of hormone-sensitive and importantly hormone-refractory prostate cancers in humans. PMID:18316193

  10. Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines.

    Science.gov (United States)

    Nakamura, Keiichiro; Yasunaga, Yutaka; Segawa, Takehiko; Ko, Daejin; Moul, Judd W; Srivastava, Shiv; Rhim, Johng S

    2002-10-01

    Curcumin, traditionally used as a seasoning spice in Indian cuisine, has been reported to decrease the proliferation potential of prostate cancer cells, by a mechanism that is not fully understood. In the current study, we have evaluated the effects of curcumin in cell growth, activation of signal transduction, and transforming activities of both androgen-dependent and independent cell lines. Prostate cancer cell lines, LNCaP and PC-3, were treated with curcumin and its effects were further analyzed on signal transduction and expression of androgen receptor (AR) and AR-related cofactors using transient transfection assay and Western blotting. Our results show that curcumin down-regulates transactivation and expression of AR, activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), and CREB (cAMP response element-binding protein)-binding protein (CBP). Curcumin also inhibited the transforming activities of both cell lines as evidenced by the reduced colony forming ability in soft agar. The results obtained here demonstrate that curcumin has a potential therapeutic effect on prostate cancer cells through down-regulation of AR and AR-related cofactors (AP-1, NF-kappaB and CBP). PMID:12239622

  11. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  12. Exosomes from the tumor microenvironment as reciprocal regulators that enhance prostate cancer progression.

    Science.gov (United States)

    Liu, Che-Ming; Hsieh, Chia-Ling; Shen, Chia-Ning; Lin, Cheng-Chieh; Shigemura, Katsumi; Sung, Shian-Ying

    2016-09-01

    Distant organ metastasis of prostate cancer is a puzzle, and various theories have successively arisen to explain the mechanism of lethal cancer progression. While perhaps agreeable to many cancer biologists, the very statement of "seed and soil" proposed by Stephan Paget in 1881 is arguably still the major statement for organ-specific cancer metastasis. Since recent studies showed important correlations of regulation of cancer cells and the microenvironment, exosomes from cancer and stromal cells seem to create another important niche for metastasis. Stromal cells pretreated with exosomes from metastatic cancer cells increase the potential of change stromal cells. The poorly metastatic cancer cells could also enhance malignancy through transfer of proteins, microribonucleic acid and messenger ribonucleic acid to recipient cancer cells. Herein, we reviewed extracellular exosomes as a factor involved in cross-talk between stromal and prostate cancer epithelial cells. PMID:27397852

  13. Expression of apoptosis-regulating genes in the rat prostate following botulinum toxin type a injection

    Directory of Open Access Journals (Sweden)

    Gorgal Tiago

    2012-01-01

    Full Text Available Abstract Background Onabotulinumtoxin A (OnabotA injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia. An OnabotA - induced volume reduction caused by sympathetic fibers impairment has been proposed as a potential mechanism of action. Our aim was to investigate the expression of apoptosis-regulating proteins in the rat prostate following OnabotA intraprostatic injection. Methods Adult Wistar rats were injected in the ventral lobes of the prostate with 10 U of OnabotA or saline. A set of OnabotA-injected animals was further treated with 0.5 mg/kg of phenylephrine (PHE subcutaneously daily. All animals were sacrificed after 1 week and had their prostates harvested. Immunohistochemical staining was performed for Bax, Bcl-xL and caspase-3 proteins and visualized by the avidin-biotin method. The optical density of the glandular cells was also determined, with measurement of differences between average optical densities for each group. Results Saline-treated animals showed intense epithelial staining for Bcl-xL and a faint labelling for both Bax and Caspase-3. OnabotA-treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline-treated animals. PHE-treated animals showed a stronger Bcl-xL staining and reduced staining of both Bax and Caspase-3 when compared to the OnabotA group. Mean signal intensity measurements for each immunoreaction confirmed a significant decrease of the signal intensity for Bcl-xL and a significant increase of the signal intensity for Bax and Caspase 3 in OnabotA-injected animals when compared with the control group. In OnabotA+PHE treated animals mean signal intensity for Bcl-xL, Bax and Caspase 3 immunoreactions was identical to that of the control animals. Conclusions These results support the hypothesis that OnabotA activates apoptotic pathways in the rat prostate through a

  14. miR-708/LSD1 axis regulates the proliferation and invasion of breast cancer cells.

    Science.gov (United States)

    Ma, Lin; Ma, Shan; Zhao, Guimei; Yang, Longqiu; Zhang, Peng; Yi, Qingting; Cheng, Shuguang

    2016-04-01

    Breast cancer is one of the most common malignant tumors in women worldwide. The microRNAs (miRNAs) are small, noncoding RNAs that regulate various biological processes, including breast cancer. miR-708 played an important role in a variety of cancers. However, its involvement in breast cancer remains largely unclear. In this study, we found that forced the expression of miR-708 in breast cancer cell lines decreased cell proliferation and invasion, whereas inhibition of miR-708 increased cell growth and invasion. miR-708 could directly target the LSD1 3'UTR to downregulate the expression. Further studies suggested that inhibition of LSD1 could phenocopied function of the miR-708 overexpression in MDA-MB-231 cells .Overexpression of LSD1 could counteract the effects of miR-708 on the proliferation and invasion. Taken together, the results indicate that miR-708 may function as a tumor suppressor gene in breast cancer development, and miR-708/LSD1 axis may be a therapeutic intervention in breast cancer in the future. PMID:26833707

  15. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells

    OpenAIRE

    David J. DeGraff; Aguiar, Adam A.; Chen, Qian; Adams, Lisa K.; Williams, B. Jill; Sikes, Robert A.

    2010-01-01

    The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment...

  16. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

    Institute of Scientific and Technical Information of China (English)

    Isabelle Bisson; David M Prowse

    2009-01-01

    Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their abil-ity to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heteroge-neous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treat-ment with WNT inhibitors reduced both prostasphere size and self-renewal, In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are con-sistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen re-ceptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit am-plifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell charac-teristics and improve the therapeutic outcome.

  17. Sex and stress steroids in adolescence: Gonadal regulation of the hypothalamic-pituitary-adrenal axis in the rat.

    Science.gov (United States)

    Green, Matthew R; McCormick, Cheryl M

    2016-08-01

    This review provides an overview of the current understanding of the role of the hypothalamic-pituitary-gonadal (HPG) axis in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. HPA function is influenced by both organizational (programming) and activational effects of gonadal hormones. Typically, in adult rats, estradiol increases and androgens decrease the HPA response to stressors, thereby contributing to sex differences in HPA function, and sensitivity of the HPA axis to gonadal steroids is in part determined by exposure to these hormones in early development. Although developmental differences in HPA function are well characterized, the extent to which gonadal steroids contribute to age differences in HPA function is not well understood. Deficits in the understanding of the relationships between the HPA and HPG axes are greatest for the adolescent period of development. The critical outstanding questions are, when do gonadal hormones begin to regulate HPA function in adolescence, and what mechanisms precipitate change in sensitivity of the HPA axis to the HPG axis at this stage of life. PMID:26851306

  18. The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells.

    Science.gov (United States)

    Zhang, Lin; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin

    2015-04-01

    Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). PMID:25645929

  19. PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation

    OpenAIRE

    Strand, D.W.; Jiang, M; Murphy, T A; Yi, Y.; Konvinse, K C; Franco, O E; Wang, Y.; Young, J D; Hayward, S.W.

    2012-01-01

    Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithel...

  20. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis.

    Science.gov (United States)

    Razzaque, Mohammed S; Lanske, Beate

    2007-07-01

    Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23-klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1alpha-hydroxylase and sodium-phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23-klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23-klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology. PMID:17592015

  1. Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models.

    Science.gov (United States)

    Yakar, Shoshana; Isaksson, Olle

    2016-06-01

    The growth hormone (GH) and its downstream mediator, the insulin-like growth factor-1 (IGF-1), construct a pleotropic axis affecting growth, metabolism, and organ function. Serum levels of GH/IGF-1 rise during pubertal growth and associate with peak bone acquisition, while during aging their levels decline and associate with bone loss. The GH/IGF-1 axis was extensively studied in numerous biological systems including rodent models and cell cultures. Both hormones act in an endocrine and autocrine/paracrine fashion and understanding their distinct and overlapping contributions to skeletal acquisition is still a matter of debate. GH and IGF-1 exert their effects on osteogenic cells via binding to their cognate receptor, leading to activation of an array of genes that mediate cellular differentiation and function. Both hormones interact with other skeletal regulators, such as sex-steroids, thyroid hormone, and parathyroid hormone, to facilitate skeletal growth and metabolism. In this review we summarized several rodent models of the GH/IGF-1 axis and described key experiments that shed new light on the regulation of skeletal growth by the GH/IGF-1 axis. PMID:26432542

  2. CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Choi, Hanbyeul; Lee, Sang Hyup; Um, Soo-Jong; Kim, Eun-Joo

    2016-07-01

    The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding. Depletion of CACUL1 enhances the LSD1 occupancy of the AR-target promoter, accompanied by decreased accumulation of H3K9me2, a repressive transcriptional marker. CACUL1 and LSD1 oppositely regulate CDX-induced cell death in AR-positive LNCaP and metastatic castrate-resistant LNCaP-LN3 cells. These data suggest that CACUL1 impairs LSD1-mediated activation of AR, thereby implicating it as a potential antitumor target in PCa. PMID:27085459

  3. Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway.

    Science.gov (United States)

    Yao, Jingjing; Xu, Chen; Fang, Ziyu; Li, Yaoming; Liu, Houqi; Wang, Yue; Xu, Chuanliang; Sun, Yinghao

    2016-05-20

    MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibit apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3'UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. PMID:27109471

  4. An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis

    Science.gov (United States)

    Matkar, Smita; Sharma, Paras; Gao, Shubin; Gurung, Buddha; Katona, Bryson W; Liao, Jennifer; Muhammad, Abdul Bari; Kong, Xiang-Cheng; Wang, Lei; Jin, Guanghui; Dang, Chi; Hua, Xianxin

    2016-01-01

    SUMMARY Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2+ cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, Lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically, in concert with a cascade of MLL2-associating epigenetic regulators, to dampen sensitivity of the cancer cells to Lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with Lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy. PMID:26461093

  5. FSH and TSH in the Regulation of Bone Mass: The Pituitary/Immune/Bone Axis

    OpenAIRE

    Graziana Colaianni; Concetta Cuscito; Silvia Colucci

    2013-01-01

    Recent evidences have highlighted that the pituitary hormones have profound effects on bone, so that the pituitary-bone axis is now becoming an important issue in the skeletal biology. Here, we discuss the topical evidence about the dysfunction of the pituitary-bone axis that leads to osteoporotic bone loss. We will explore the context of FSH and TSH hormones arguing their direct or indirect role in bone loss. In addition, we will focus on the knowledge that both FSH and TSH have influence on...

  6. Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

    Directory of Open Access Journals (Sweden)

    Gupta Aditi

    2012-09-01

    Full Text Available Abstract Background Bone loss and pathological fractures are common skeletal complications associated with androgen deprivation therapy and bone metastases in prostate cancer patients. We have previously demonstrated that prostate cancer cells secrete receptor activator of NF-kB ligand (RANKL, a protein essential for osteoclast differentiation and activation. However, the mechanism(s by which RANKL is produced remains to be determined. The objective of this study is to gain insight into the molecular mechanisms controlling RANKL expression in metastatic prostate cancer cells. Results We show here that phosphorylation of Smad 5 by integrin αvβ3 and RUNX2 by CD44 signaling, respectively, regulates RANKL expression in human-derived PC3 prostate cancer cells isolated from bone metastasis. We found that RUNX2 intranuclear targeting is mediated by phosphorylation of Smad 5. Indeed, Smad5 knock-down via RNA interference and inhibition of Smad 5 phosphorylation by an αv inhibitor reduced RUNX2 nuclear localization and RANKL expression. Similarly, knockdown of CD44 or RUNX2 attenuated the expression of RANKL. As a result, conditioned media from these cells failed to support osteoclast differentiation in vitro. Immunohistochemistry analysis of tissue microarray sections containing primary prostatic tumor (grade2-4 detected predominant localization of RUNX2 and phosphorylated Smad 5 in the nuclei. Immunoblotting analyses of nuclear lysates from prostate tumor tissue corroborate these observations. Conclusions Collectively, we show that CD44 signaling regulates phosphorylation of RUNX2. Localization of RUNX2 in the nucleus requires phosphorylation of Smad-5 by integrin αvβ3 signaling. Our results suggest possible integration of two different pathways in the expression of RANKL. These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer.

  7. Cosuppression of Sprouty and Sprouty-Related Negative Regulators of FGF Signalling in Prostate Cancer: A Working Hypothesis

    Directory of Open Access Journals (Sweden)

    Stephen J. Assinder

    2015-01-01

    Full Text Available Deregulation of FGF receptor tyrosine kinase (RTK signalling is common in prostate cancer. Normally, to moderate RTK signalling, induction of Sprouty (SPRY and Sprouty-related (SPRED antagonists occurs. Whilst decreased SPRY and SPRED has been described in some cancers, their role in prostate cancer is poorly understood. Therefore, we hypothesise that due to the need for tight regulation of RTK signalling, SPRY and SPRED negative regulators provide a degree of redundancy which ensures that a suppression of one or more family member does not lead to disease. Contrary to this, our analyses of prostates from 24-week-old Spry1- or Spry2-deficientmice, either hemizygous (+/− or homozygous (−/− for the null allele, revealed a significantly greater incidence of PIN compared to wild-type littermates. We further investigated redundancy of negative regulators in the clinical setting in a preliminary analysis of Gene Expression Omnibus and Oncomine human prostate cancer datasets. Consistent with our hypothesis, in two datasets analysed a significant cosuppression of SPRYs and SPREDs is evident. These findings demonstrate the importance of negative regulators of receptor tyrosine signalling, such as Spry, in the clinical setting, and highlight their importance for future pharmacopeia.

  8. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein

    OpenAIRE

    Yiwei Li; Mingxin Che; Sunita Bhagat; Kerrie-Lynn Ellis; Omer Kucuk; Doerge, Daniel R.; Judith Abrams; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  9. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein1

    OpenAIRE

    Li, Yiwei; Che, Mingxin; Bhagat, Sunita; Ellis, Kerrie-Lynn; KUCUK, Omer; Doerge, Daniel R.; Abrams, Judith; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  10. PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer

    International Nuclear Information System (INIS)

    Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell–cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E-cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell–cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway

  11. CXCR4 expression in prostate cancer progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anna Dubrovska

    Full Text Available Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44(+/CD133(+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy.

  12. Specific changes in the expression of imprinted genes in prostate cancer-implications for cancer progression and epigenetic regulation

    Institute of Scientific and Technical Information of China (English)

    Teodora Ribarska; Klaus-Marius Bastian; Annemarie Koch; Wolfgang A Schulz

    2012-01-01

    Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation,enhancer of zeste homologue 2 (EZH2)overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer.DNA methylation,EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes.Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes,expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2).A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms.Instead,selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes,which might function in the prostate to limit cell growth induced viathe PI3K/Akt pathway,modulate androgen responses and regulate differentiation.Whereas dysregulation of IG F2 may constitute an early change in prostate carcinogenesis,inactivation of this imprinted gene network is rather associated with cancer progression.

  13. Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Yue [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China); Du, Chengli [Department of Hepatobiliary Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (China); Wang, Bo; Zhang, Yanling; Liu, Xiaoyan [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China); Ren, Guoping, E-mail: renguoping12345@163.com [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China)

    2014-07-18

    Highlights: • The expression of eEF1A2 is up-regulated in prostate cancer tissues. • Suppression of eEF1A2 inhibits the proliferation and promotes apoptosis. • Inhibition of eEF1A2 enhances the expression of apoptotic relevant proteins. • The expressions of eEF1A2 and cleavage-caspase3 are inversely correlated. - Abstract: Background: eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. Methods: We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Results: Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Conclusion: Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer.

  14. Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer

    International Nuclear Information System (INIS)

    Highlights: • The expression of eEF1A2 is up-regulated in prostate cancer tissues. • Suppression of eEF1A2 inhibits the proliferation and promotes apoptosis. • Inhibition of eEF1A2 enhances the expression of apoptotic relevant proteins. • The expressions of eEF1A2 and cleavage-caspase3 are inversely correlated. - Abstract: Background: eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. Methods: We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Results: Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Conclusion: Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer

  15. Role of the hypothalamic–pituitary–thyroid axis in metabolic regulation by JNK1

    OpenAIRE

    Sabio, Guadalupe; Cavanagh-Kyros, Julie; Barrett, Tamera; Jung, Dae Young; Ko, Hwi Jin; Ong, Helena; Morel, Caroline; Mora, Alfonso; Reilly, Judith; Kim, Jason K.; Davis, Roger J

    2010-01-01

    The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic–pituitary–thyroid axis. Disruption of thyroid hormone function prev...

  16. Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors.

    Science.gov (United States)

    Mir, Hina; Kapur, Neeraj; Singh, Rajesh; Sonpavde, Guru; Lillard, James W; Singh, Shailesh

    2016-01-01

    Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB(-/-)) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa. PMID:27029529

  17. Regulation mechanisms of pituitary-thyroid axis in normal subjects and patients with Graves' disease

    International Nuclear Information System (INIS)

    The regulatory mechanism of the pituitary-thyroid axis in normal subjects and patients with Graves' disease was investigated using a highly sensitive TSH assay based on the immunoradiometric assay. All of the normal subjects had detectable TSH values within the range 0.35 to 6.0 μU/ml. No negative correlations between TSH and free thyroid hormones existed in normal subjects. Patients with thyroid carcinoma who seemed to have normal pituitary-thyroid function showed a rapid increase of TSH after total thyroidectomy. On the other hand, while untreated patients with Graves' disease all had undetectable TSH values, these patients took 1 to 3.5 months longer to normalize their TSH values than to normalize free thyroid hormones on antithyroid drug therapy. During the recovery phase by the treatment with decrease of antithyroid drug or supplement of T4 from iatrogenic hypothyroid state after treatment for Graves' disease and thyroid carcinoma, normalization of TSH levels was delayed than that of free thyroid hormones. Patients with Graves' disease in remission showed an extremely positive correlation between basal and peak TSH levels in TRH test, and a negative correlation between basal TSH and FT4. In conclusion, an individual patient may have a different set point concerning the regulatory mechanism of the pituitary-thyroid axis, and the persistence of the hyperthyroid state would seem to have caused some reversible dysfunction of the pituitary gland. (author)

  18. The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice

    Directory of Open Access Journals (Sweden)

    Edoardo Balzani

    2016-07-01

    Full Text Available An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3Sci/+, we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3Sci/+ mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms and the seconds-to-minutes scale (i.e., anticipating behavioral responses in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3Sci/+-dependent network.

  19. Regulation of DU145 prostate cancer cell growth by Scm-like with four mbt domains 2

    Indian Academy of Sciences (India)

    Kwanghyun Lee; Wonho Na; Je-Heon Maeng; Hongjin Wu; Bong-Gun Ju

    2013-03-01

    Mammalian SFMBTs have been considered to be polycomb group repressors. However, molecular mechanisms underlying mammalian SFMBTs-mediated gene regulation and their biological function have not been characterized. In the present study, we identified YY1 and methylated histones as interacting proteins of human SFMBT2. We also found that human SFMBT2 binds preferentially to methylated histone H3 and H4 that are associated with transcriptional repression. Using DU145 prostate cancer cells as a model, we showed that SFMBT2 has a transcriptional repression activity on HOXB13 gene expression. In addition, occupancy of SFMBT2 coincided with enrichment of diand tri-methylated H3K9 and H4K20 as well as tri-methylated H3K27 at the HOXB13 gene promoter. When SFMBT2 was depleted by siRNA in DU145 prostate cancer cells, significant up-regulation of HOXB13 gene expression and decreased cell growth were observed. Collectively, our findings indicate that human SFMBT2 may regulate cell growth via epigenetic regulation of HOXB13 gene expression in DU145 prostate cancer cells.

  20. TBK1 Regulates Prostate Cancer Dormancy through mTOR Inhibition

    Directory of Open Access Journals (Sweden)

    Jin Koo Kim

    2013-09-01

    Full Text Available The mechanisms that regulate hematopoietic stem cell (HSC dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa cells target the HSC niche in mouse bone marrow (BM during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1 on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.

  1. Weight loss by calorie restriction versus bariatric surgery differentially regulates the HPA axis in male rats

    Science.gov (United States)

    Grayson, Bernadette E.; Hakala-Finch, Andrew P.; Kekulawala, Melani; Laub, Holly; Egan, Ann E.; Ressler, Ilana B.; Woods, Stephen C.; Herman, James P.; Seeley, Randy J.; Benoit, Stephen C.; Ulrich-Lai, Yvonne M.

    2015-01-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in 5 groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n=7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n=11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n=11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n=11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n=12). Compared to Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentrations and increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results suggest that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  2. Nesfatin-1 regulates the hypothalamo-pituitary-ovarian axis of fish.

    Science.gov (United States)

    Gonzalez, Ronald; Shepperd, Erin; Thiruppugazh, Vetri; Lohan, Sneha; Grey, Caleb L; Chang, John P; Unniappan, Suraj

    2012-10-01

    Nesfatin-1 is an anorexigen in goldfish. In the present study, we provide novel data indicating the presence and regulatory effects of nesfatin-1 on the hypothalamo-pituitary-ovarian (HPO) axis of goldfish. Nucleobindin-2 (NUCB2)/nesfatin-1-like immunoreactive (ir) cells are present in the hypothalamus and in the pituitary, suggesting a hypophysiotropic role for nesfatin-1. NUCB2/nesfatin-1-like ir cells colocalize gonadotropin-releasing hormone (GnRH) in the nucleus lateralis tuberis posterioris and the nucleus anterior tuberis of the goldfish hypothalamus. The presence of nesfatin-1 with GnRH in these two nuclei implicated in pituitary hormone release suggests a role for nesfatin-1 on gonadotropin secretion. A single i.p. injection of synthetic goldfish nesfatin-1 (50 ng/g body wt) resulted in an acute decrease (∼75%) in the expression of hypothalamic chicken GnRH-II and salmon GnRH mRNAs at 15 min postinjection in goldfish. Meanwhile, pituitary luteinizing hormone (LH) beta and follicle-stimulating hormone beta mRNAs were also inhibited (∼80%), but only at 60 min postinjection. Nesfatin-1 administration also resulted in a significant reduction (∼60%) in serum LH levels at 60 min postadministration. Nesfatin-1-like immunoreactivity was also found in the follicle cells, but not the oocytes, in zebrafish and goldfish ovaries. Incubation of zebrafish follicles with nesfatin-1 resulted in a significant reduction in basal germinal vesicle breakdown (∼50%) during the oocyte maturation. In addition, nesfatin-1 also attenuated the stimulatory effects of maturation-inducing hormone on germinal vesicle breakdown. Together, the current results indicate that nesfatin-1 is a metabolic hormone with an inhibitory tone on fish reproduction. Nesfatin-1 appears to elicit this suppressive effect through actions on all three tissues in the fish HPO axis. PMID:22895855

  3. The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer

    OpenAIRE

    Kashyap, Vasundhra; Ahmad, Shafqat; Nilsson, Emeli M.; Helczynski, Leszek; Kenna, Sinéad; Persson, Jenny Liao; Gudas, Lorraine J.; Nigel P. Mongan

    2013-01-01

    Recurrent prostate cancer remains a major clinical challenge. The lysine specific demethylase-1 (LSD1/KDM1A), together with the JmjC domain-containing JMJD2A and JMJD2C proteins, have emerged as critical regulators of histone lysine methylation. The LSD1-JMJD2 complex functions as a transcriptional co-regulator of hormone activated androgen and estrogen receptors at specific gene promoters. LSD1 also regulates DNA methylation and p53 function. LSD1 is overexpressed in numerous cancers includi...

  4. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    International Nuclear Information System (INIS)

    Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to

  5. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  6. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Victor Villar

    2013-01-01

    Full Text Available Purpose. To determine whether Ski-interacting protein (SKIP regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA, matrix metalloproteinase-9 (MMP-9, and uPA Inhibitor (PAI-1 in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

  7. Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis.

    Science.gov (United States)

    Winnick, Jason J; Kraft, Guillaume; Gregory, Justin M; Edgerton, Dale S; Williams, Phillip; Hajizadeh, Ian A; Kamal, Maahum Z; Smith, Marta; Farmer, Ben; Scott, Melanie; Neal, Doss; Donahue, E Patrick; Allen, Eric; Cherrington, Alan D

    2016-06-01

    Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion. PMID:27140398

  8. Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle

    Science.gov (United States)

    Roa, Wilson; Zhang, Xiaojing; Guo, Linghong; Shaw, Andrew; Hu, Xiuying; Xiong, Yeping; Gulavita, Sunil; Patel, Samir; Sun, Xuejun; Chen, Jie; Moore, Ronald; Xing, James Z.

    2009-09-01

    Glucose-capped gold nanoparticles (Glu-GNPs) have been used to improve cellular targeting and radio-sensitization. In this study, we explored the mechanism of Glu-GNP enhanced radiation sensitivity in radiation-resistant human prostate cancer cells. Cell survival and proliferation were measured using MTT and clonogenic assay. Flow cytometry with staining by propidium iodide (PI) was performed to study the cell cycle changes induced by Glu-GNPs, and western blotting was used to determine the expression of p53 and cyclin proteins that correlated to cell cycle regulation. With 2 Gy of ortho-voltage irradiation, Glu-GNP showed a 1.5-2.0 fold enhancement in growth inhibition when compared to x-rays alone. Comparing the cell cycle change, Glu-GNPs induced acceleration in the G0/G1 phase and accumulation of cells in the G2/M phase at 29.8% versus 18.4% for controls at 24 h. G2/M arrest was accompanied by decreased expression of p53 and cyclin A, and increased expression of cyclin B1 and cyclin E. In conclusion, Glu-GNPs trigger activation of the CDK kinases leading to cell cycle acceleration in the G0/G1 phase and accumulation in the G2/M phase. This activation is accompanied by a striking sensitization to ionizing radiation, which may have clinical implications.

  9. A protein in rat prostatic chromatin interacting with androgen regulated gene

    Institute of Scientific and Technical Information of China (English)

    XUYOUHAI; RONGCHANG; 等

    1992-01-01

    2M NaCl-insoluble fraction of rat ventral Prostate chromatin(residual proteins)contain proteins able to interact specifically with androgen-receptor complex and is ,therefore,a part of the aceptor complex.Among residual proteins a 98 KDa protein has been found which binds significantly to a genomic fiagment containing an androgen-regulated gene coding for a 22 KDa protein The biological significance of this binding in androgen action need to be further studied.A mini-plasmid clone containing 22 KDa protein coding sequence was cloned into charon 4A genomic library from which a 5.7 Kb genomic fragment was isolated,identified by hybridization with a 5' and a 3' cDNA probes,and shown to contain the 3' flanking sequence.Restriction enzyme treatment of this fragment yielded a 4.7 Kb restriction fragmwent representing the 5' upstream region and a 1.0 Kb containing part of the coding sequence.Deletion studies indicated that the 97 KDa protein bound only to a subclone of about 300 bp segment .Furthermore,gel shifting experiment supported its DNA-protein binding.

  10. Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex.

    Science.gov (United States)

    Marins, Fernanda Ribeiro; Limborço-Filho, Marcelo; Xavier, Carlos Henrique; Biancardi, Vinicia C; Vaz, Gisele C; Stern, Javier E; Oppenheimer, Stephen M; Fontes, Marco Antonio Peliky

    2016-04-01

    Cardiovascular (CV) representation has been identified within the insular cortex (IC) and a lateralization of function previously suggested. In order to further understand the role of IC on cardiovascular control, the present study compared the CV responses evoked by stimulation of N-metil-D-aspartate (NMDA) receptors in the right and left posterior IC at different rostrocaudal levels. Intracortical microinjections of NMDA were performed into the IC of male Wistar rats anaesthetized with urethane (1.4 g/kg) prepared for blood pressure, heart rate and renal sympathetic nerve activity. Gene expression of NMDA receptor subunits NR2A and NR2B in the IC was confirmed by RT-PCR. Immunofluorescence for the NMDA receptor NR1 subunit was demonstrated in the IC (coordinates anteroposterior (AP) +1.5, 0.0 and -1.5 mm). A cardiac sympathoinhibitory site was identified, more rostrally located than identified in previous studies. A site of sympathoexcitatory cardiac control was identified more caudal to this region in agreement with earlier work. Under the experimental conditions, no lateralization of cardiovascular function was identified with chemical stimulation eliciting the same responses from either left or right insular cortices. No tonic role of the insula on cardiovascular control was identified with the use of the NMDA antagonist, AP-5. Peri-insular microinjection of NMDA was without cardiovascular effect indicating the specificity of the insula as a cardiovascular regulatory site. The current study reveals a functional topography for autonomic cardiovascular control along the rostrocaudal axis of the posterior IC. PMID:26748663

  11. Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells12

    Science.gov (United States)

    Wittig-Blaich, Stephanie M; Kacprzyk, Lukasz A; Eismann, Thorsten; Bewerunge-Hudler, Melanie; Kruse, Petra; Winkler, Eva; Strauss, Wolfgang S L; Hibst, Raimund; Steiner, Rudolf; Schrader, Mark; Mertens, Daniel; Sültmann, Holger; Wittig, Rainer

    2011-01-01

    The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases. PMID:21750652

  12. Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Stephanie M Wittig-Blaich

    2011-07-01

    Full Text Available The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases.

  13. The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

    OpenAIRE

    Haxhinasto, Sokol; Mathis, Diane; Benoist, Christophe

    2008-01-01

    CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially dimi...

  14. VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis.

    Science.gov (United States)

    Groppa, Elena; Brkic, Sime; Bovo, Emmanuela; Reginato, Silvia; Sacchi, Veronica; Di Maggio, Nunzia; Muraro, Manuele G; Calabrese, Diego; Heberer, Michael; Gianni-Barrera, Roberto; Banfi, Andrea

    2015-10-01

    VEGF is widely investigated for therapeutic angiogenesis, but while short-term delivery is desirable for safety, it is insufficient for new vessel persistence, jeopardizing efficacy. Here, we investigated whether and how VEGF dose regulates nascent vessel stabilization, to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF, but delayed or prevented by higher doses, without affecting pericyte coverage. Rather, VEGF dose-dependently inhibited endothelial Semaphorin3A expression, thereby impairing recruitment of Neuropilin-1-expressing monocytes (NEM), TGF-β1 production and endothelial SMAD2/3 activation. TGF-β1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression, thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF-β1 was necessary to start the Semaphorin3A/NEM axis. Conversely, Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenoviral delivery. Therefore, VEGF inhibits the endothelial Semaphorin3A/NEM/TGF-β1 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF-induced angiogenesis. PMID:26323572

  15. Prostate specific membrane antigen (PSMA regulates angiogenesis independently of VEGF during ocular neovascularization.

    Directory of Open Access Journals (Sweden)

    Christina L Grant

    Full Text Available BACKGROUND: Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti-angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF. While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies. METHODOLOGY/PRINCIPAL FINDINGS: Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature. CONCLUSIONS/SIGNIFICANCE: Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may

  16. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Regulates the Hypothalamo-Pituitary-Thyroid (HPT) Axis via Type 2 Deiodinase in Male Mice.

    Science.gov (United States)

    Egri, P; Fekete, C; Dénes, Á; Reglődi, D; Hashimoto, H; Fülöp, B D; Gereben, Balázs

    2016-06-01

    The hypothalamic activation of thyroid hormones by type 2 deiodinase (D2), catalyzing the conversion of thyroxine to T3, is critical for the proper function of the hypothalamo-pituitary-thyroid (HPT) axis. Regulation of D2 expression in tanycytes alters the activity of the HPT axis. However, signals that regulate D2 expression in tanycytes are poorly understood. The pituitary adenylate cyclase-activating polypeptide (PACAP) increases intracellular cAMP level, a second messenger known to stimulate the DIO2 gene; however, its importance in tanycytes is not completely characterized. Therefore, we tested whether this ubiquitously expressed neuropeptide regulates the HPT axis through stimulation of D2 in tanycytes. PACAP increased the activity of human DIO2 promoter in luciferase reporter assay that was abolished by mutation of cAMP-response element. Furthermore, PAC1R receptor immunoreactivity was identified in hypothalamic tanycytes, suggesting that these D2-expressing cells could be regulated by PACAP. Intracerebroventricular PACAP administration resulted in increased D2 activity in the mediobasal hypothalamus, suppressed Trh expression in the hypothalamic paraventricular nucleus, and decreased Tshb expression in the pituitary demonstrating that PACAP affects the D2-mediated control of the HPT axis. To understand the role of endogenous PACAP in the regulation of HPT axis, the effect of decreased PACAP expression was studied in heterozygous Adcyap1 (PACAP) knockout mice. These animals were hypothyroid that may be the consequence of altered hypothalamic T3 degradation during set-point formation of the HPT axis. In conclusion, PACAP is an endogenous regulator of the HPT axis by affecting T3-mediated negative feedback via cAMP-induced D2 expression of tanycytes. PMID:27046436

  17. Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    YE Ding-wei; LI Hui; TSENG Jane; CHAUVIN Priscilla; QIAN Song-xi; ZHENG Jia-fu; SUN Ying-hao; MA Yong-jiang

    2002-01-01

    Objective: To explore the possible mechanisms of growth regression of human androgen dependentprostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1×10-9mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulationmolecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cellline LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Humanandrogen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regula-tion of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially inLNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased con-tinuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclu-sion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation moleculeschanges, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinomaafter androgen ablation by either operative or medicine methods.

  18. First pharmacophore-based identification of androgen receptor down-regulating agents: discovery of potent anti-prostate cancer agents.

    Science.gov (United States)

    Purushottamachar, Puranik; Khandelwal, Aakanksha; Chopra, Pankaj; Maheshwari, Neha; Gediya, Lalji K; Vasaitis, Tadas S; Bruno, Robert D; Clement, Omoshile O; Njar, Vincent C O

    2007-05-15

    A qualitative 3D pharmacophore model (a common feature based model or Catalyst HipHop algorithm) was developed for well-known natural product androgen receptor down-regulating agents (ARDAs). The four common chemical features identified included: one hydrophobic group, one ring aromatic group, and two hydrogen bond acceptors. This model served as a template in virtual screening of the Maybridge and NCI databases that resulted in identification of six new ARDAs (EC(50) values 17.5-212 microM). Five of these molecules strongly inhibited the growth of human prostate LNCaP cells. These novel compounds may be used as leads to develop other novel anti-prostate cancer agents. PMID:17383188

  19. Vitamin D3 regulates the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Linda Kelsey

    Full Text Available 1α-25(OH2 vitamin D3 (1-25D, an active hormonal form of Vitamin D3, is a well-known chemopreventive and pro-differentiating agent. It has been shown to inhibit the growth of several prostate cancer cell lines. Gap junctions, formed of proteins called connexins (Cx, are ensembles of cell-cell channels, which permit the exchange of small growth regulatory molecules between adjoining cells. Cell-cell communication mediated by gap junctional channels is an important homeostatic control mechanism for regulating cell growth and differentiation. We have investigated the effect of 1-25D on the formation and degradation of gap junctions in an androgen-responsive prostate cancer cell line, LNCaP, which expresses retrovirally-introduced Cx32. Connexin32 is expressed by the luminal and well-differentiated cells of normal prostate and prostate tumors. Our results document that 1-25D enhances the expression of Cx32 and its subsequent assembly into gap junctions. Our results further show that 1-25D prevents androgen-regulated degradation of Cx32, post-translationally, independent of androgen receptor (AR-mediated signaling. Finally, our findings document that formation of gap junctions sensitizes Cx32-expressing LNCaP cells to the growth inhibitory effects of 1-25D and alters their morphology. These findings suggest that the growth-inhibitory effects of 1-25D in LNCaP cells may be related to its ability to modulate the assembly of Cx32 into gap junctions.

  20. Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

    OpenAIRE

    Zhang, Xinhua; Zang, Ning; Wei, Yu; Yin, Jin; Teng, Ruobing; Seftel, Allen; DiSanto, Michael E.

    2011-01-01

    Testosterone (T) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementa...

  1. Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia.

    Science.gov (United States)

    Grabowska, Magdalena M; Kelly, Stephen M; Reese, Amy L; Cates, Justin M; Case, Tom C; Zhang, Jianghong; DeGraff, David J; Strand, Douglas W; Miller, Nicole L; Clark, Peter E; Hayward, Simon W; Gronostajski, Richard M; Anderson, Philip D; Matusik, Robert J

    2016-03-01

    A functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia. PMID:26677878

  2. The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability

    Directory of Open Access Journals (Sweden)

    Benoit Miotto

    2014-04-01

    Full Text Available Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability.

  3. Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease.

    Science.gov (United States)

    Zhong, Jixin; Rajagopalan, Sanjay

    2015-01-01

    Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed protease that regulates diverse number of physiological functions. As a dipeptidase, it exerts its catalytic effects on proteins/peptides with proline, alanine, or serine in the penultimate (P1) amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is perhaps an increasingly recognized target, given its importance in processes, such as hematopoiesis, angiogenesis, and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease. PMID:26441982

  4. Regulation of Akt/FOXO3a/GSK-3β/AR Signaling Network by Isoflavone in Prostate Cancer Cells*

    OpenAIRE

    Li, Yiwei; Wang, Zhiwei; Kong, Dejuan; Li, Ran; Sarkar, Sanila H.; Sarkar, Fazlul H

    2008-01-01

    We have previously shown that genistein could inhibit Akt activation and down-regulate AR (androgen receptor) and PSA (prostate-specific antigen) expression in prostate cancer (PCa) cells. However, pure genistein showed increased lymph node metastasis in an animal model, but such an adverse effect was not seen with isoflavone, suggesting that further mechanistic studies are needed for elucidating the role of isoflavone in PCa. It is known that FOXO3a and GSK-3β, target...

  5. A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

    International Nuclear Information System (INIS)

    Purpose: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials: PTEN wild-type (PTEN+/+) and PTEN knockout (PTEN−/−) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN−/− cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results: PTEN−/− cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN−/− cells demonstrated increased clonogenic survival in vitro compared to PTEN+/+, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN−/− cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN−/− cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions: We propose that PDGF D represents a potentially promising

  6. DIPEPTIDYL PEPTIDASE-4 REGULATION OF SDF-1/CXCR4 AXIS: IMPLICATIONS FOR CARDIOVASCULAR DISEASE

    Directory of Open Access Journals (Sweden)

    Jixin eZhong

    2015-09-01

    Full Text Available Dipeptidyl peptidase-4 (DPP4 is a ubiquitously expressed protease that regulates a diverse number of physiologic functions. As a dipeptidase it exerts its catalytic effects on proteins/peptides with proline, alanine or serine in the penultimate (P1 amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which such as stromal-cell-derived factor-1 (SDF-1, also known as CXCL12 is perhaps an increasingly recognized target, given its importance in processes such as hematopoiesis, angiogenesis and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease.

  7. Drosophila Syncrip binds the gurken mRNA localisation signal and regulates localised transcripts during axis specification

    Directory of Open Access Journals (Sweden)

    Suzanne M. McDermott

    2012-04-01

    In the Drosophila oocyte, mRNA transport and localised translation play a fundamental role in axis determination and germline formation of the future embryo. gurken mRNA encodes a secreted TGF-α signal that specifies dorsal structures, and is localised to the dorso-anterior corner of the oocyte via a cis-acting 64 nucleotide gurken localisation signal. Using GRNA chromatography, we characterised the biochemical composition of the ribonucleoprotein complexes that form around the gurken mRNA localisation signal in the oocyte. We identified a number of the factors already known to be involved in gurken localisation and translational regulation, such as Squid and Imp, in addition to a number of factors with known links to mRNA localisation, such as Me31B and Exu. We also identified previously uncharacterised Drosophila proteins, including the fly homologue of mammalian SYNCRIP/hnRNPQ, a component of RNA transport granules in the dendrites of mammalian hippocampal neurons. We show that Drosophila Syncrip binds specifically to gurken and oskar, but not bicoid transcripts. The loss-of-function and overexpression phenotypes of syncrip in Drosophila egg chambers show that the protein is required for correct grk and osk mRNA localisation and translational regulation. We conclude that Drosophila Syncrip is a new factor required for localisation and translational regulation of oskar and gurken mRNA in the oocyte. We propose that Syncrip/SYNCRIP is part of a conserved complex associated with localised transcripts and required for their correct translational regulation in flies and mammals.

  8. Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

    International Nuclear Information System (INIS)

    Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APP has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes

  9. Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Toshiaki; Ikeda, Kazuhiro; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan)

    2014-09-26

    Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APP has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.

  10. Protective Effects of Berberine on Isoproterenol-Induced Acute Myocardial Ischemia in Rats through Regulating HMGB1-TLR4 Axis

    Directory of Open Access Journals (Sweden)

    Tianzhu Zhang

    2014-01-01

    Full Text Available Berberine, an isoquinoline alkaloid originally isolated from the Chinese herb Coptis chinensis (Huanglian, has been shown to display a wide array of pharmacological activities. The present study was to investigate the effects of berberine against myocardial ischemia produced in rats by isoproterenol. 50 male Sprague-Dawley rats were randomized equally into five groups: a control group, an untreated model group, berberine (30, 60 mg/kg treatment, or propranolol (30 mg/kg. Rats were treated for 12 days and then given isoproterenol, 85 mg/kg for 2 consecutive days by subcutaneous injection. ST-segment elevation was measured after the last administration. Serum levels of creatine kinase isoenzyme (CK-MB, lactate dehydrogenase (LDH, tumor necrosis factor-α (TNF-α, and interleukin-6 (IL-6 were measured after the rats were sacrificed. The hearts were excised for determining heart weight index, microscopic examination, high mobility group box 1 (HMGB1, toll-like receptor (TLR4, prodeath protein (Bax, antideath protein (Bcl-2, and tumor necrosis factor (TNF-α protein were determined by western blot. Berberine decreased the ST elevation induced by acute myocardial ischemia, and decreased serum levels of CK-MB, LDH, TNF-α, and IL-6. Berberine increased total superoxide dismutase (T-SOD activity and decreased malondialdehyde (MDA content in myocardial tissue. Berberine can regulate HMGB1-TLR4 axis to protect myocardial ischemia.

  11. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.

    Science.gov (United States)

    Clarke, G; Grenham, S; Scully, P; Fitzgerald, P; Moloney, R D; Shanahan, F; Dinan, T G; Cryan, J F

    2013-06-01

    Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life. PMID:22688187

  12. Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133a Axis.

    Directory of Open Access Journals (Sweden)

    Aude Angelini

    Full Text Available Myocardial fibrosis contributes to the remodeling of heart and the loss of cardiac function leading to heart failure. SRF is a transcription factor implicated in the regulation of a large variety of genes involved in cardiac structure and function. To investigate the impact of an SRF overexpression in heart, we developed a new cardiac-specific and tamoxifen-inducible SRF overexpression mouse model by the Cre/loxP strategy. Here, we report that a high level overexpression of SRF leads to severe modifications of cardiac cytoarchitecture affecting the balance between cardiomyocytes and cardiac fibroblasts and also a profound alteration of cardiac gene expression program. The drastic development of fibrosis was characterized by intense sirius red staining and associated with an increased expression of genes encoding extracellular matrix proteins such as fibronectin, procollagen type 1α1 and type 3α1 and especially connective tissue growth factor (CTGF. Furthermore miR-133a, one of the most predominant cardiac miRNAs, is strongly downregulated when SRF is overexpressed. By comparison a low level overexpression of SRF has minor impact on these different processes. Investigation with miR-133a, antimiR-133a and AdSRF-VP16 experiments in H9c2 cardiac cells demonstrated that: 1-miR-133a acts as a repressor of SRF and CTGF expression; 2-a simultaneous overexpression of SRF by AdSRF-VP16 and inhibition of miR-133a by a specific antimiR increase CTGF expression; 3-miR-133a overexpression can block the upregulation of CTGF induced by AdSRF-VP16. Taken together, these findings reveal a key role of the SRF/CTGF/miR-133a axis in the regulation of cardiac fibrosis.

  13. Gonadotropin Inhibitory Hormone Down-Regulates the Brain-Pituitary Reproductive Axis of Male European Sea Bass (Dicentrarchus labrax).

    Science.gov (United States)

    Paullada-Salmerón, José A; Cowan, Mairi; Aliaga-Guerrero, María; Morano, Francesca; Zanuy, Silvia; Muñoz-Cueto, José A

    2016-06-01

    Gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin synthesis and release from the pituitary of birds and mammals. However, the physiological role of orthologous GnIH peptides on the reproductive axis of fish is still uncertain, and their actions on the main neuroendocrine systems controlling reproduction (i.e., GnRHs, kisspeptins) have received little attention. In a recent study performed in the European sea bass, we cloned a cDNA encoding a precursor polypeptide that contained C-terminal MPMRFamide (sbGnIH-1) and MPQRFamide (sbGnIH-2) peptide sequences, developed a specific antiserum against sbGnIH-2, and characterized its central and pituitary GnIH projections in this species. In this study, we analyzed the effects of intracerebroventricular injection of sbGnIH-1 and sbGnIH-2 on brain and pituitary expression of reproductive hormone genes (gnrh1, gnrh2, gnrh3, kiss1, kiss2, gnih, lhbeta, fshbeta), and their receptors (gnrhr II-1a, gnrhr II-2b, kiss1r, kiss2r, and gnihr) as well as on plasma Fsh and Lh levels. In addition, we determined the effects of GnIH on pituitary somatotropin (Gh) expression. The results obtained revealed the inhibitory role of sbGnIH-2 on brain gnrh2, kiss1, kiss2, kiss1r, gnih, and gnihr transcripts and on pituitary fshbeta, lhbeta, gh, and gnrhr-II-1a expression, whereas sbGnIH-1 only down-regulated brain gnrh1 expression. However, at different doses, central administration of both sbGnIH-1 and sbGnIH-2 decreased Lh plasma levels. Our work represents the first study reporting the effects of centrally administered GnIH in fish and provides evidence of the differential actions of sbGnIH-1 and sbGnIH-2 on the reproductive axis of sea bass, the main inhibitory role being exerted by the sbGnIH-2 peptide. PMID:26984999

  14. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    International Nuclear Information System (INIS)

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  15. Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway.

    Directory of Open Access Journals (Sweden)

    Saurabh Singh

    Full Text Available Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA. Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP, Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell

  16. Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression

    International Nuclear Information System (INIS)

    Metastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143. The expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo. These data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer

  17. The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer

    Directory of Open Access Journals (Sweden)

    Meyer Hellmuth-Alexander

    2008-12-01

    Full Text Available Abstract Background The three far-upstream element (FUSE binding proteins (FBP1, FBP2, and FBP3 belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear. Methods FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays. Results High rates of FBP1 and FBP3 expression were observed in all cancer types. There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p Conclusion The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors.

  18. Berberine Ameliorates Nonbacterial Prostatitis via Multi-Target Metabolic Network Regulation

    OpenAIRE

    Sun, Hui; Wang, Huiyu; Zhang, Aihua; Yan, Guangli; Zhang, Yue; An, Na; Wang, Xijun

    2015-01-01

    Metabolomics has been increasingly applied to discovering biomarkers and identifying perturbed pathways. Berberine has been shown to exhibit anti-inflammatory, antioxidant, and anticancer properties, but its mechanisms for treating nonbacterial prostatitis (NBP) remain unclear completely. We developed the untargeted metabolomics approach based on UPLC-Q-TOF-HDMS to profile the metabolite changes in urine samples in order to discover novel potential biomarkers to clarify mechanisms of berberin...

  19. Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer

    International Nuclear Information System (INIS)

    Understanding the complex, multistep process of metastasis remains a major challenge in cancer research. Metastasis models can reveal insights in tumor development and progression and provide tools to test new intervention strategies. To develop a new cancer metastasis model, we used DU145 human prostate cancer cells and performed repeated rounds of orthotopic prostate injection and selection of subsequent lymph node metastases. Tumor growth, metastasis, cell migration and invasion were analyzed. Microarray analysis was used to identify cell migration- and cancer-related genes correlating with metastasis. Selected genes were silenced using siRNA, and their roles in cell migration and invasion were determined in transwell migration and Matrigel invasion assays. Our in vivo cycling strategy created cell lines with dramatically increased tumorigenesis and increased ability to colonize lymph nodes (DU145LN1-LN4). Prostate tumor xenografts displayed increased vascularization, enlarged podoplanin-positive lymphatic vessels and invasive margins. Microarray analysis revealed gene expression profiles that correlated with metastatic potential. Using gene network analysis we selected 3 significantly upregulated cell movement and cancer related genes for further analysis: EPCAM (epithelial cell adhesion molecule), ITGB4 (integrin β4) and PLAU (urokinase-type plasminogen activator (uPA)). These genes all showed increased protein expression in the more metastatic DU145-LN4 cells compared to the parental DU145. SiRNA knockdown of EpCAM, integrin-β4 or uPA all significantly reduced cell migration in DU145-LN4 cells. In contrast, only uPA siRNA inhibited cell invasion into Matrigel. This role of uPA in cell invasion was confirmed using the uPA inhibitors, amiloride and UK122. Our approach has identified genes required for the migration and invasion of metastatic tumor cells, and we propose that our new in vivo model system will be a powerful tool to interrogate the metastatic

  20. Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2

    Czech Academy of Sciences Publication Activity Database

    Pernicová, Zuzana; Slabáková, Eva; Kharaishvili, G.; Bouchal, J.; Král, M.; Kunická, Z.; Machala, M.; Kozubík, Alois; Souček, Karel

    2011-01-01

    Roč. 13, č. 6 (2011), s. 526-536. ISSN 1522-8002 R&D Projects: GA ČR(CZ) GA310/07/0961; GA MZd NS9600; GA MZd NS9956 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : prostate cancer * senescence * Skp2 Subject RIV: BO - Biophysics Impact factor: 5.946, year: 2011

  1. Disorder, Promiscuous Interactions, and Stochasticity Regulate State Switching in the Unstable Prostate.

    Science.gov (United States)

    Kulkarni, Prakash; Getzenberg, Robert H

    2016-10-01

    A causal link between benign prostatic hyperplasia (BPH) and prostate cancer has long been suspected but not widely accepted. A new model is proposed that supports such a connection. In contrast to the prevailing wisdom, our model, that draws on dynamical systems theory, suggests that in response to stress, epithelial cells in the unstable gland can give rise to both types of diseases via a phenotypic switching mechanism. The central idea is that phenotypic switching is a stochastic process which exploits the plasticity of the epithelial cell. It is driven by 'noise' contributed by the conformational dynamics of proteins that are intrinsically disordered. In a system that is noisy when stressed, disorder promotes promiscuity, unmasks latent information, and rewires the network to cause phenotypic switching. Cells with newly acquired phenotypes can transcend the traditional zonal boundaries to give rise to BPH or prostate cancer depending on the microenvironment. Establishing causality between the two diseases may provide us with an opportunity to better understand their etiology and guide prevention and treatment strategies. J. Cell. Biochem. 117: 2235-2240, 2016. © 2016 Wiley Periodicals, Inc. PMID:27152744

  2. A role for the androgen metabolite, 5alpha androstane 3beta, 17beta diol (3β-diol) in the regulation of the hypothalamo-pituitary-adrenal axis.

    Science.gov (United States)

    Handa, Robert J; Sharma, Dharmendra; Uht, Rosalie

    2011-01-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3β-Diol in

  3. A Role for the Androgen Metabolite, 5alpha androstane, 3beta, 17beta Diol (3b-DIol in the regulation of the hypothalamo-pituitary-adrenal axis.

    Directory of Open Access Journals (Sweden)

    Robert James Handa

    2011-11-01

    Full Text Available Activation of the hypothalamo-pituitary-adrenal (HPA axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus of the hypothalamus (PVN. Within the PVN, corticotropin-releasing hormone (CRH, vasopressin (AVP and oxytocin (OT expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2 and testosterone (T are well known reproductive hormones, however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated ACTH and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen, dihydrotestosterone, whereas E2 effects were thought to be mediated by both estrogen receptors alpha (ERα and beta (ERβ. However, DHT has been shown to be metabolized to the ERβ agonist, 5alpha- androstane 3beta,17beta diol (3b-Diol. The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta knockout mice. The neurobiological mechanisms underlying the actions of ERbeta to alter HPA reactivity are not currently known. CRH, AVP and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters have been shown by 3β-Diol binding to ERbeta and this is thought to be through alternate pathways of gene regulation. Based on available data, a novel and important role for 3beta Diol in the regulation of the HPA axis is suggested.

  4. A Role for the Androgen Metabolite, 5alpha Androstane 3beta, 17beta Diol (3β-Diol) in the Regulation of the Hypothalamo-Pituitary–Adrenal Axis

    Science.gov (United States)

    Handa, Robert J.; Sharma, Dharmendra; Uht, Rosalie

    2011-01-01

    Activation of the hypothalamo-pituitary–adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3

  5. MiR-128b is down-regulated in gastric cancer and negatively regulates tumour cell viability by targeting PDK1/Akt/NF-κB axis

    Indian Academy of Sciences (India)

    Ling Zhang; Jun Lei; Zi-Ling Fang; Jian-Ping Xiong

    2016-03-01

    Gastric cancer (GC) is the fourth most prevalent type of cancer worldwide, which is usually caused by the interaction between environmental and genetic factors, or epigenetic aspects. Referring to the non-coding RNAs, miR-128b has been reported to be associated with many tumour cases, and exerts distinct functions in different types of cancers. However, the function of miR-128b in GC onset and progression largely remains unknown. In the present study, we found that miR-128b expression was down-regulated in tissues from 18 GC patients and 3 carcinoma cell lines. In turn, over-expression of miR-128b suppressed GC cell proliferation, invasion and promoted apoptosis. Moreover, miR-128b was predicted to bind the 3'UTR of PDK1 gene using bioinformatic target-screening tools. Accordingly, ectopic expression of miR-128b inhibited the PDK1 expression at both transcriptional and post-transcriptional levels, and furthermore, the expression of gene tailed by the 3′UTR of PDK1 gene was significantly decreased in a dualluciferase reporter assay, suggesting that PDK1 was a direct target of miR-128b in GC cells. In the conditon of miR-128b over-expression, we also observed spontaneous inactivation of the Akt/NF-κB signalling, implying PDK1 was a potential regulator of this pathway. In conclusion, our study shed some novel light on miR-128b-PDK1/Akt/NF-κB axis on GC progression.

  6. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer

    International Nuclear Information System (INIS)

    Transcriptional profiling of prostate cancer (PC) has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH). The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms

  7. The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer

    International Nuclear Information System (INIS)

    The three far-upstream element (FUSE) binding proteins (FBP1, FBP2, and FBP3) belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear. FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays. High rates of FBP1 and FBP3 expression were observed in all cancer types. There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p < 0.001 both). C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p < 0.001 and 0.09 resp.), but not in bladder or prostate cancer. The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors

  8. Regulation of osteoclast differentiation by the TGFbeta proteins secreted by prostate cancer cells

    Czech Academy of Sciences Publication Activity Database

    Vaňhara, P.; Lincová, Eva; Souček, Karel; Šmarda, J.

    Singapore, 2008. s. 89. [Keystone Symposia on Molecular and Cellular Biology, Stem Cells, Cancer and Aging, Swissotel the Stamford/Biopolis. 29.09.2008-04.10.2008, Singapore] R&D Projects: GA ČR(CZ) GA301/06/0036; GA ČR(CZ) GD204/08/H054; GA ČR(CZ) GA204/07/0834; GA ČR(CZ) GA310/07/0961 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : osteoclast differentiation * TGF-beta * prostate cancer Subject RIV: BO - Biophysics

  9. Down-regulation of ATM Protein Sensitizes Human Prostate Cancer Cells to Radiation-induced Apoptosis*

    OpenAIRE

    Truman, Jean-Philip; Gueven, Nuri; Lavin, Martin; Leibel, Steven; Kolesnick, Richard; Fuks, Zvi; Haimovitz-Friedman, Adriana

    2005-01-01

    Treatment with the protein kinase C activator 12-O tetradecanoylphorbol 12-acetate (TPA) enables radiation-resistant LNCaP human prostate cancer cells to undergo radiation-induced apoptosis, mediated via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto, M., Haimovitz-Friedman, A., Liao, W. C., White-Jones, M., Huryk, R., Heston, D. W. W., Cardon-Cardo, C., Kolesnick, R., and Fuks, Z. (1999) Cancer Res. 59, 5194-5201). Here, we show t...

  10. Down-Regulation of Notch-1 Is Associated With Akt and FoxM1 in Inducing Cell Growth Inhibition and Apoptosis in Prostate Cancer Cells

    OpenAIRE

    Wang, Zhiwei; Li, Yiwei; Ahmad, Aamir; Banerjee, Sanjeev; Azmi, Asfar S; Kong, Dejuan; Wojewoda, Christine; Miele, Lucio; Sarkar, Fazlul H

    2011-01-01

    Although many studies have been done to uncover the mechanisms by which down-regulation of Notch-1 exerts its anti-tumor activity against a variety of human malignancies, the precise molecular mechanisms remain unclear. In the present study, we investigated the cellular consequence of Notch-1 down-regulation and also assessed the molecular consequence of Notch-1-mediated alterations of its downstream targets on cell viability and apoptosis in prostate cancer (PCa) cells. We found that the dow...

  11. 动物GH/IGF-Ⅰ轴调控机制的研究进展%Advances on the Regulation Mechanism of Growth Hormone/IGF- Ⅰ Axis

    Institute of Scientific and Technical Information of China (English)

    顾志良; 王慧娟; 郁建锋

    2011-01-01

    生长轴是动物体内下丘脑—垂体—靶器官一系列激素及其受体所组成的神经内分泌系统.通过提高生长轴中生长激素(GH)和胰岛素样生长因子-Ⅰ (IGF-Ⅰ)水平,促进增重、提高饲料转化率和改善肉品质,是畜禽生长调控的一种新途径.GH通过IGF-Ⅰ介导调节动物生长和细胞分化等,文章综述了GH/IGF-Ⅰ轴的组成、功能,以及GH调控IGF-Ⅰ表达的分子机理.%The growth axis is a neuroendocrine system, which is composed of series of hormones and their receptors from the hypothalamus-pituitary-target organ in xrivo of animals. Increasing the GH and IGF- I levels in the growth axis, to promote weight gain, feed conversion rate and improve meat quality, which is a new approach of animal growth regulation. GH mediated by IGF- I regulates animal growth and cell differentiation. We will discuss the constitution and function of GH/IGF-I axis, and mechanism of growth hormone regulation of IGF- I expression in this review.

  12. Regulation of cholesterol 25-hydroxylase expression by vitamin D3 metabolites in human prostate stromal cells

    International Nuclear Information System (INIS)

    Vitamin D3 plays an important role in the control of cell proliferation and differentiation. Cholesterol 25-hydroxylase (CH25H) is an enzyme converting cholesterol into 25-hydroxycholesterol. Vitamin D3 as well as 25-hydroxycholesterol has been shown to inhibit cell growth and induce cell apoptosis. Here we show that 10 nM 1α,25(OH)2D3 and 500 nM 25OHD3 upregulate CH25H mRNA expression in human primary prostate stromal cells (P29SN). Protein synthesis inhibitor cycloheximide does not block 1α,25(OH)2D3 mediated upregulation of CH25H mRNA. Transcription inhibitor actinomycin D blocks basal level as well as 1α,25(OH)2D3 induced CH25H mRNA expression. 1α,25(OH)2D3 has no effect on CH25H mRNA stability. 25-Hydroxycholesterol significantly decreased the P29SN cell number. A CH25H enzyme inhibitor, desmosterol, increases basal cell number but has no significant effect on vitamin D3 treated cells. Our data suggest that ch25h could be a vitamin D3 target gene and may partly mediate anti-proliferative action of vitamin D3 in human primary prostate stromal cells

  13. Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs

    International Nuclear Information System (INIS)

    Recent evidence suggests that the prostate cancer (PCa)-specific up-regulation of certain genes such as AMACR, EZH2, PSGR, PSMA and TRPM8 could be associated with an aberrant expression of non-coding microRNAs (miRNA). In silico analyses were used to search for miRNAs being putative regulators of PCa-associated genes. The expression of nine selected miRNAs (hsa-miR-101, -138, -186, -224, -26a, -26b, -374a, -410, -660) as well as of the aforementioned PCa-associated genes was analyzed by quantitative PCR using 50 malignant (Tu) and matched non-malignant (Tf) tissue samples from prostatectomy specimens as well as 30 samples from patients with benign prostatic hyperplasia (BPH). Then, correlations between paired miRNA and target gene expression levels were analyzed. Furthermore, the effect of exogenously administered miR-26a on selected target genes was determined by quantitative PCR and Western Blot in various PCa cell lines. A luciferase reporter assay was used for target validation. The expression of all selected miRNAs was decreased in PCa tissue samples compared to either control group (Tu vs Tf: -1.35 to -5.61-fold; Tu vs BPH: -1.17 to -5.49-fold). The down-regulation of most miRNAs inversely correlated with an up-regulation of their putative target genes with Spearman correlation coefficients ranging from -0.107 to -0.551. MiR-186 showed a significantly diminished expression in patients with non-organ confined PCa and initial metastases. Furthermore, over-expression of miR-26a reduced the mRNA and protein expression of its potential target gene AMACR in vitro. Using the luciferase reporter assay AMACR was validated as new target for miR-26a. The findings of this study indicate that the expression of specific miRNAs is decreased in PCa and inversely correlates with the up-regulation of their putative target genes. Consequently, miRNAs could contribute to oncogenesis and progression of PCa via an altered miRNA-target gene-interaction

  14. Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer.

    Science.gov (United States)

    Darimipourain, M; Wang, S; Ittmann, M; Kwabi-Addo, B

    2011-12-01

    Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post-transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3'UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches. PMID:21826097

  15. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion

    International Nuclear Information System (INIS)

    Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation

  16. Direct regulation of LAMP1 by tumor-suppressive microRNA-320a in prostate cancer

    Science.gov (United States)

    OKATO, ATSUSHI; GOTO, YUSUKE; KUROZUMI, AKIRA; KATO, MAYUKO; KOJIMA, SATOKO; MATSUSHITA, RYOSUKE; YONEMORI, MASAYA; MIYAMOTO, KAZUTAKA; ICHIKAWA, TOMOHIKO; SEKI, NAOHIKO

    2016-01-01

    Advanced prostate cancer (PCa) metastasizes to bone and lymph nodes, and currently available treatments cannot prevent the progression and metastasis of the disease. Therefore, an improved understanding of the molecular mechanisms of the progression and metastasis of advanced PCa using current genomic approaches is needed. Our miRNA expression signature in castration-resistant prostate cancer (CRPC) revealed that microRNA-320a (miR-320a) was significantly reduced in cancer tissues, suggesting that miR-320a may be a promising anticancer miRNA. The aim of this study was to investigate the functional roles of miR-320a in naïve PCa and CRPC cells and to identify miR-320a-regulated genes involved in PCa metastasis. The expression levels of miR-320a were significantly reduced in naïve PCa, CRPC specimens, and PCa cell lines. Restoration of mature miR-320a in PCa cell lines showed that miR-320a significantly inhibited cancer cell migration and invasion. Moreover, we found that lysosomal-associated membrane protein 1 (LAMP1) was a direct target of miR-320a in PCa cells. Silencing of LAMP1 using siRNA significantly inhibited cell proliferation, migration, and invasion in PCa cells. Overexpression of LAMP1 was observed in PCa and CRPC clinical specimens. Moreover, downstream pathways were identified using si-LAMP1-transfected cells. The discovery of tumor-suppressive miR-320a-mediated pathways may provide important insights into the potential mechanisms of PCa metastasis. PMID:27212625

  17. Impact of TGIFLX Expression on the Regulation of BCL2 and BAX in Prostate Cancer Cell Line (LNCaP)

    OpenAIRE

    Raoofian, Reza; Mojarrad, Majid; Heidari, Mansour; Sciences, Tehran, Iran.

    2013-01-01

    Aims: The homeoprotein TGIFLX (transforming growth factor-β-induced factor 2-like, Xlinked), which is essential in male reproduction and development and likely oncogenic when aberrantly expressed in prostate. We have previously shown an aberrant expression of TGIFLX in the majority of human prostate tumors. However, mechanism by which TGIFLX acts in prostate cancer is unknown. The aim of this study was to investigate the effects of overexpression of wild-type TGIFLX (wt-TGIFLX) on LNCaP,...

  18. The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

    OpenAIRE

    Lin ZHANG; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M.; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin

    2015-01-01

    Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to t...

  19. C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion.

    Science.gov (United States)

    Barakat, David J; Mendonca, Janet; Barberi, Theresa; Zhang, Jing; Kachhap, Sushant K; Paz-Priel, Ido; Friedman, Alan D

    2016-05-28

    The purpose of this study was to ascertain the mechanisms by which advanced prostate cancer cells resist bortezomib therapy. Several independent studies have shown that cells are protected from proteasome inhibition by increased autophagic activity. We investigated whether C/EBPβ, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBPβ, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBPβ knockdown suppressed autophagosome-lysosome fusion. We also found that C/EBPβ knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBPβ levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBPβ sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBPβ. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBPβ knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBPβ is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy. PMID:26968249

  20. Bioactive compounds from Paecilomyces tenuipes regulating the function of the hypothalamo-hypophyseal system axis in chronic unpredictable stress rats

    Institute of Scientific and Technical Information of China (English)

    YIN Yan-yan; MING Liang; ZHENG Li-fang; KAN Hong-wei; LI Chun-ru; LI Wei-ping

    2007-01-01

    Background A bioactive compound from Paecilomyces tenuipes (BGPT) has an inhibitory effect on monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) in vitro and in vivo, which indicates BCPT may be a potential antidepressant. In this study we aimed to study the antidepressant effects of BCPT in the chronic unpredictable stress(CUS) model in rats and explore underlying mechanisms in the hypothalamic-pituitary-adrenal (HPA) axis.Methods The antidepressant effects of BCPT were studied in the chronic unpredictable stress model in rats. Animals were housed isolated, except the control group. Rats were exposed daily to different random stressors from day 1 to 21.Awarding response was detected by calculating the 24-hour consumption of sucrose water. Cortisol (CORT) and adrenocorticotropic hormone (ATCH) contents in serum and arginine vasopressin (AVP) contents in the pituitary body were detected by radio immunoassays. Total RNA of hippocampus or hypothalamus was extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR) for the measurement of corticotrophin releasing hormone(CRH) mRNA or mineralocorticoid receptor (MR) mRNA and glucocorticoid receptor (GR) mRNA levels. Statistical analyses were performed using one way analysis of variance (ANOVA) followed by Student-Newman-Keuls (SNK) test.Results Chronic unpredictable stress resulted in reduction of sensitivity to reward and abnormality in the HPA axis in the animal model. BCPT improved the reward reaction as measured by increasing sucrose consumption, remarkably reduced serum CORT and ACTH levels and the AVP content in the pituitary body in the CUS-treated rats, decreased the expression of CRH mRNA, enhanced the expression of hippocampus MR mRNA, GR mRNA and decreased the ratio of MR/GR.Conclusions BCPT has potentially antidepressant-like activity and normalized the HPA axis hyperactivity in a CUS model of depression in rats. This may be an important mechanism of its antidepressant effect.

  1. microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression

    International Nuclear Information System (INIS)

    Highlights: • miR-218 expression is downregulated in prostate cancer. • miR-218 inhibits prostate tumor cells proliferation partially through promoting apoptosis. • miR-218 targets TPD52 by binding to its 3′-UTR. • miR-218 suppresses prostate cancer cell growth through inhibiting TPD52 expression. - Abstract: The tumor protein D52 (TPD52) is an oncogene overexpressed in prostate cancer (PC) due to gene amplification. Although the oncogenic effect of TPD52 is well recognized, how its expression is regulated is still not clear. This study tried to explore the regulative role of miR-218, a tumor suppressing miRNA on TPD52 expression and prostate cancer cell proliferation. We found the expression of miR-218 was significantly lower in PC specimens. Based on gain and loss of function analysis, we found miR-218 significantly inhibit cancer cell proliferation by inducing apoptosis. These results strongly suggest that miR-218 plays a tumor suppressor role in PC cells. In addition, our data firstly demonstrated that miR-218 directly regulates oncogenic TPD52 in PC3 cells and the miR-218-TPD52 axis can regulate growth of this prostate cancer cell line. Knockdown of TPD52 resulted in significantly increased cancer cell apoptosis. Clearly understanding of oncogenic TPD52 pathways regulated by miR-218 might be helpful to reveal new therapeutic targets for PC

  2. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

    Directory of Open Access Journals (Sweden)

    Marie Lundholm

    Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  3. Differential regulation of glutathione S—transferase Yb1 mRNA levels in rat prostate,liver and brain by androgen

    Institute of Scientific and Technical Information of China (English)

    ZHANGYUAN; CHAWNSHANGCHANG; 等

    1995-01-01

    Northern blot analysis of glutathione S-transferase (GST)Yb1 mRNA in different tissues of male and female rate revealed that its tissue-specific transcription patterns were highly sex hormone related.Although the GST Yb1 mRNA could be detected in most of the tissues examined at various levels,the highest abundance was observed in the ventral prostate,uterus and liver,which were the main the ventral prostate,uterus and liver,which were the main target tissue for androgen,estrogen and glucocorticoid respectively.The effect of androgen on the transcription of GST YB1 was also tissue-specific.Since androgen with drawal by castration caused the up-regulation of GST Yb1 mRNA in the ventral prostate but down-regulation in the liver and no effect in the brain,evalution of this system for studying the regulation mechanisms of gene expression by which androgen exerts its differential effects has been discussed.

  4. Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression.

    Directory of Open Access Journals (Sweden)

    Weiwei Huang

    Full Text Available Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine, have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1 was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa.

  5. A potential kidney-bone axis involved in the rapid minute-to-minute regulation of plasma Ca2+

    DEFF Research Database (Denmark)

    Nordholm, Anders; Mace, Maria L; Gravesen, Eva; Olgaard, Klaus; Lewin, Ewa

    2015-01-01

    BACKGROUND: Understanding the regulation of mineral homeostasis and function of the skeleton as buffer for Calcium and Phosphate has regained new interest with introduction of the syndrome "Chronic Kidney Disease-Mineral and Bone Disorder"(CKD-MBD). The very rapid minute-to-minute regulation of p...

  6. E2F1 promotes tumor cell invasion and migration through regulating CD147 in prostate cancer.

    Science.gov (United States)

    Liang, Yu-Xiang; Lu, Jian-Ming; Mo, Ru-Jun; He, Hui-Chan; Xie, Jian; Jiang, Fu-Neng; Lin, Zhuo-Yuan; Chen, Yan-Ru; Wu, Yong-Ding; Luo, Hong-Wei; Luo, Zheng; Zhong, Wei-De

    2016-04-01

    Increased expression of E2F1 has been reported to be associated with tumor growth and cell survival of prostate cancer (PCa). However, its roles and mechanisms on PCa have not been fully elucidated. The present study found that E2F1 overexpression in PCa tissues was significantly associated with high Gleason score (P=0.01) and advanced pathological stage (P=0.02). In addition, PCa patients with high E2F1 expression more frequently had shorter biochemical recurrence-free survival (P=0.047) than those with low E2F1 expression. Then, we confirmed that the knock-down of E2F1 expression was able to inhibit cell cycle progression, invasion and migration of PCa cell lines in vitro, along with tumor xenograft growth and epithelial-to-mesenchymal transition (EMT) in vivo. Moreover, we identified CD147 as a novel interaction partner for E2F1 through bio-informatic binding site prediction, combined with chromatin immunoprecipitation-PCR (ChIP-PCR) and western blot analysis. Taken together, our data delineate an as yet unrecognized function of E2F1 as enhancer of tumor invasion and migration of PCa via regulating the expression of CD147 in PCa. Importantly, E2F1 may function as a biomarker that can differentiate patients with biochemical recurrent and non-biochemical recurrent disease following radical prostatectomy, highlighting its potential as a therapeutic target. PMID:26891801

  7. The Nrf1 and Nrf2 Balance in Oxidative Stress Regulation and Androgen Signaling in Prostate Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, Michelle A. [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Abdel-Mageed, Asim B. [Department of Urology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Mondal, Debasis, E-mail: dmondal@tulane.edu [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States)

    2010-06-21

    Reactive oxygen species (ROS) signaling has recently sparked a surge of interest as being the molecular underpinning for cancer cell survival, but the precise mechanisms involved have not been completely elucidated. This review covers the possible roles of two ROS-induced transcription factors, Nrf1 and Nrf2, and the antioxidant proteins peroxiredoxin-1 (Prx-1) and Thioredoxin-1 (Txn-1) in modulating AR expression and signaling in aggressive prostate cancer (PCa) cells. In androgen independent (AI) C4-2B cells, in comparison to the parental androgen dependent (AD) LNCaP cells, we present evidence of high Nrf1 and Prx-1 expression and low Nrf2 expression in these aggressive PCa cells. Furthermore, in DHT treated C4-2B cells, increased expression of the p65 (active) isoform of Nrf1 correlated with enhanced AR transactivation. Our findings implicate a crucial balance of Nrf1 and Nrf2 signaling in regulating AR activity in AI-PCa cells. Here we will discuss how understanding the mechanisms by which oxidative stress may affect AR signaling may aid in developing novel therapies for AI-PCa.

  8. The Nrf1 and Nrf2 Balance in Oxidative Stress Regulation and Androgen Signaling in Prostate Cancer Cells

    International Nuclear Information System (INIS)

    Reactive oxygen species (ROS) signaling has recently sparked a surge of interest as being the molecular underpinning for cancer cell survival, but the precise mechanisms involved have not been completely elucidated. This review covers the possible roles of two ROS-induced transcription factors, Nrf1 and Nrf2, and the antioxidant proteins peroxiredoxin-1 (Prx-1) and Thioredoxin-1 (Txn-1) in modulating AR expression and signaling in aggressive prostate cancer (PCa) cells. In androgen independent (AI) C4-2B cells, in comparison to the parental androgen dependent (AD) LNCaP cells, we present evidence of high Nrf1 and Prx-1 expression and low Nrf2 expression in these aggressive PCa cells. Furthermore, in DHT treated C4-2B cells, increased expression of the p65 (active) isoform of Nrf1 correlated with enhanced AR transactivation. Our findings implicate a crucial balance of Nrf1 and Nrf2 signaling in regulating AR activity in AI-PCa cells. Here we will discuss how understanding the mechanisms by which oxidative stress may affect AR signaling may aid in developing novel therapies for AI-PCa

  9. D-Glucosamine down-regulates HIF-1{alpha} through inhibition of protein translation in DU145 prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jee-Young; Park, Jong-Wook; Suh, Seong-Il [Chronic Disease Research Center, School of Medicine, Keimyung University, 194 Dongsan-Dong, Jung-Gu, Daegu 700-712 (Korea, Republic of); Baek, Won-Ki, E-mail: wonki@dsmc.or.kr [Chronic Disease Research Center, School of Medicine, Keimyung University, 194 Dongsan-Dong, Jung-Gu, Daegu 700-712 (Korea, Republic of)

    2009-04-24

    D-Glucosamine has been reported to inhibit proliferation of cancer cells in culture and in vivo. In this study we report a novel response to D-glucosamine involving the translation regulation of hypoxia inducible factor (HIF)-1{alpha} expression. D-Glucosamine caused a decreased expression of HIF-1{alpha} under normoxic and hypoxic conditions without affecting HIF-1{alpha} mRNA expression in DU145 prostate cancer cells. D-Glucosamine inhibited HIF-1{alpha} accumulation induced by proteasome inhibitor MG132 and prolyl hydroxylase inhibitor DMOG suggesting D-glucosamine reduces HIF-1{alpha} protein expression through proteasome-independent pathway. Metabolic labeling assays indicated that D-glucosamine inhibits translation of HIF-1{alpha} protein. In addition, D-glucosamine inhibited HIF-1{alpha} expression induced by serum stimulation in parallel with inhibition of p70S6K suggesting D-glucosamine inhibits growth factor-induced HIF-1{alpha} expression, at least in part, through p70S6K inhibition. Taken together, these results suggest that D-glucosamine inhibits HIF-1{alpha} expression through inhibiting protein translation and provide new insight into a potential mechanism of the anticancer properties of D-glucosamine.

  10. D-Glucosamine down-regulates HIF-1α through inhibition of protein translation in DU145 prostate cancer cells

    International Nuclear Information System (INIS)

    D-Glucosamine has been reported to inhibit proliferation of cancer cells in culture and in vivo. In this study we report a novel response to D-glucosamine involving the translation regulation of hypoxia inducible factor (HIF)-1α expression. D-Glucosamine caused a decreased expression of HIF-1α under normoxic and hypoxic conditions without affecting HIF-1α mRNA expression in DU145 prostate cancer cells. D-Glucosamine inhibited HIF-1α accumulation induced by proteasome inhibitor MG132 and prolyl hydroxylase inhibitor DMOG suggesting D-glucosamine reduces HIF-1α protein expression through proteasome-independent pathway. Metabolic labeling assays indicated that D-glucosamine inhibits translation of HIF-1α protein. In addition, D-glucosamine inhibited HIF-1α expression induced by serum stimulation in parallel with inhibition of p70S6K suggesting D-glucosamine inhibits growth factor-induced HIF-1α expression, at least in part, through p70S6K inhibition. Taken together, these results suggest that D-glucosamine inhibits HIF-1α expression through inhibiting protein translation and provide new insight into a potential mechanism of the anticancer properties of D-glucosamine.

  11. Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats.

    Science.gov (United States)

    Grayson, Bernadette E; Hakala-Finch, Andrew P; Kekulawala, Melani; Laub, Holly; Egan, Ann E; Ressler, Ilana B; Woods, Stephen C; Herman, James P; Seeley, Randy J; Benoit, Stephen C; Ulrich-Lai, Yvonne M

    2014-12-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  12. Marsdenia tenacissima extract suppresses A549 cell migration through regulation of CCR5-CCL5 axis, Rho C, and phosphorylated FAK.

    Science.gov (United States)

    Lin, Sen-Sen; Li, Fang-Fang; Sun, Li; Fan, Wei; Gu, Ming; Zhang, Lu-Yong; Qin, Song; Yuan, Sheng-Tao

    2016-03-01

    Marsdenia tenacissima, a traditional Chinese medicine, is long been used to treat various diseases including asthma, cancer, trachitis, tonsillitis, pharyngitis, cystitis, and pneumonia. Although Marsdenia tenacissima has been demonstrated to have strong anti-tumor effects against primary tumors, its effect on cancer metastasis remains to be defined, and the molecular mechanism underlying the anti-metastatic effect is unknown. In the present study, we investigated the effects of XAP (an extract of Marsdenia tenacissima) on A549 lung cancer cell migration and explored the role of CCR5-CCL5 axis in the anti-metastatic effects of XAP. Our resutls showed that XAP inhibited A549 lung cancer cell migration and invasion in a dose-dependent manner. The protein levels of CCR5, but not CCR9 and CXCR4, were decreased by XAP. The secretion of CCL5, the ligand of CCR5, was reduced by XAP. XAP down-regulated Rho C expression and FAK phosphorylation. In conclusion, XAP inhibited A549 cell migration and invasion through down-regulation of CCR5-CCL5 axis, Rho C, and FAK. PMID:27025367

  13. Regulation of Cox-2 by Cyclic AMP Response Element Binding Protein in Prostate Cancer: Potential Role for Nexrutine

    Directory of Open Access Journals (Sweden)

    Rita Ghosh

    2007-11-01

    Full Text Available We recently showed that NexrutineR, a Phellodendron amurense bark extract, suppresses proliferation of prostate cancer cell lines and tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP model. Our data also indicate that the antiproliferative effects of NexrutineR are mediated in part by Akt and Cyclic AMP response element binding protein (CREB. Cyclooxygenase (Cox-2, a pro-inflammatory mediator, is a CREB target that induces prostaglandin E2 (PGE2 and suppresses apoptosis. Treatment of LNCaP cells with NexrutineR reduced tumor necrosis factor α-induced enzymatic as well as promoter activities of Cox-2. NexrutineR also reduced the expression and promoter activity of Cox-2 in PC-3 cells that express high constitutive levels of Cox-2. Deletion analysis coupled with mutational analysis of the Cox-2 promoter identified CRE as being sufficient for mediating NexrutineR response. Immunohistochemical analysis of human prostate tumors show increased expression of CREB and DNA binding activity in high-grade tumors (three-fold higher in human prostate tumors compared to normal prostate; P = .01. We have identified CREB-mediated activation of Cox-2 as a potential signaling pathway in prostate cancer which can be blocked with a nontoxic, cost-effective dietary supplement like NexrutineR, demonstrating a prospective for development of NexrutineR for prostate cancer management.

  14. NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis.

    Science.gov (United States)

    Bagaitkar, Juhi; Pech, Nancy K; Ivanov, Stoyan; Austin, Anthony; Zeng, Melody Yue; Pallat, Sabine; Huang, Guangming; Randolph, Gwendalyn J; Dinauer, Mary C

    2015-12-17

    The leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generates reactive oxygen species essential in microbial killing and regulation of inflammation. Inactivating mutations in this enzyme lead to chronic granulomatous disease (CGD), associated with increased susceptibility to both pyogenic infections and to inflammatory disorders. The role of the NADPH oxidase in regulating inflammation driven by nonmicrobial stimuli is poorly understood. Here, we show that NADPH oxidase deficiency enhances the early local release of interleukin-1α (IL-1α) in response to damaged cells, promoting an excessive granulocyte colony-stimulating factor (G-CSF)-regulated neutrophilic response and prolonged inflammation. In peritoneal inflammation elicited by tissue injury, X-linked Cybb-null (X-CGD) mice exhibited increased release of IL-1α and IL-1 receptor -mediated G-CSF production. In turn, higher levels of systemic G-CSF increased peripheral neutrophilia, which amplified neutrophilic peritoneal inflammation in X-CGD mice. Dampening early neutrophil recruitment by neutralization of IL-1α, G-CSF, or neutrophil depletion itself promoted resolution of otherwise prolonged inflammation in X-CGD. IL-1β played little role. Thus, we identified an excessive IL-1α/G-CSF response as a major driver of enhanced sterile inflammation in CGD in the response to damaged cells. More broadly, these results provide new insights into the regulation of sterile inflammation, and identify the NADPH oxidase in regulating the amplitude of the early neutrophilic response. PMID:26443623

  15. Prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, G.P.; Kuss, R., Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results.

  16. Prostate cancer

    International Nuclear Information System (INIS)

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results

  17. Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development

    OpenAIRE

    Keil, Kimberly P.; Mehta, Vatsal; Branam, Amanda M.; Abler, Lisa L.; Buresh-Stiemke, Rita A.; Joshi, Pinak S.; Schmitz, Christopher T.; Marker, Paul C.; Vezina, Chad M.

    2012-01-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-respons...

  18. Involvement of Intercellular Adhesion Molecule-1 Up-Regulation in Bradykinin Promotes Cell Motility in Human Prostate Cancers

    Directory of Open Access Journals (Sweden)

    Chih-Hsin Tang

    2013-06-01

    Full Text Available Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Bradykinin (BK is an inflammatory mediator and has recently been shown to mediate tumor growth and metastasis. The adhesion molecule intercellular adhesion molecule-1 (ICAM-1 plays a critical role during tumor metastasis. The aim of this study was to examine whether BK promotes prostate cancer cell migration via ICAM-1 expression. The motility of cancer cells was increased following BK treatment. Stimulation of prostate cancer cells with BK induced mRNA and protein expression of ICAM-1. Transfection of cells with ICAM-1 small interfering RNA reduced BK-increased cell migration. Pretreatment of prostate cancer cells with B2 receptor, phosphatidylinositol 3-kinase (PI3K, Akt, and activator protein 1 (AP-1 inhibitors or mutants abolished BK-promoted migration and ICAM-1 expression. In addition, treatment with a B2 receptor, PI3K, or Akt inhibitor also reduced BK-mediated AP-1 activation. Our results indicate that BK enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves the B2 receptor, PI3K, Akt, and AP-1. Thus, BK represents a promising new target for treating prostate cancer metastasis.

  19. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.

    Science.gov (United States)

    Yamaguchi, Osamu; Kaneshiro, Takashi; Saitoh, Shu-ichi; Ishibashi, Toshiyuki; Maruyama, Yukio; Takeishi, Yasuchika

    2009-01-01

    We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox

  20. MicroRNA-196b regulates the homeobox B7-vascular endothelial growth factor axis in cervical cancer.

    Directory of Open Access Journals (Sweden)

    Christine How

    Full Text Available The down-regulation of microRNA-196b (miR-196b has been reported, but its contribution to cervical cancer progression remains to be investigated. In this study, we first demonstrated that miR-196b down-regulation was significantly associated with worse disease-free survival (DFS for cervical cancer patients treated with combined chemo-radiation. Secondly, using a tri-modal approach for target identification, we determined that homeobox-B7 (HOXB7 was a bona fide target for miR-196b, and in turn, vascular endothelial growth factor (VEGF was a downstream transcript regulated by HOXB7. Reconstitution of miR-196b expression by transient transfection resulted in reduced cell growth, clonogenicity, migration and invasion in vitro, as well as reduced tumor angiogenesis and tumor cell proliferation in vivo. Concordantly, siRNA knockdown of HOXB7 or VEGF phenocopied the biological effects of miR-196b over-expression. Our findings have demonstrated that the miR-196b/HOXB7/VEGF pathway plays an important role in cervical cancer progression; hence targeting this pathway could be a promising therapeutic strategy for the future management of this disease.

  1. Autonomous and nonautonomous regulation of axis formation by antagonistic signaling via 7-span cAMP receptors and GSK3 in Dictyostelium.

    Science.gov (United States)

    Ginsburg, G T; Kimmel, A R

    1997-08-15

    Early during Dictyostelium development a fundamental cell-fate decision establishes the anteroposterior (prestalk/prespore) axis. Signaling via the 7-transmembrane cAMP receptor CAR4 is essential for creating and maintaining a normal pattern; car4-null alleles have decreased levels of prestalk-specific mRNAs but enhanced expression of prespore genes. car4- cells produce all of the signals required for prestalk differentiation but lack an extracellular factor necessary for prespore differentiation of wild-type cells. This secreted factor decreases the sensitivity of prespore cells to inhibition by the prestalk morphogen DIF-1. At the cell autonomous level, CAR4 is linked to intracellular circuits that activate prestalk but inhibit prespore differentiation. The autonomous action of CAR4 is antagonistic to the positive intracellular signals mediated by another cAMP receptor, CAR1 and/or CAR3. Additional data indicate that these CAR-mediated pathways converge at the serine/threonine protein kinase GSK3, suggesting that the anterior (prestalk)/posterior (prespore) axis of Dictyostelium is regulated by an ancient mechanism that is shared by the Wnt/Fz circuits for dorsoventral patterning during early Xenopus development and establishing Drosophila segment polarity. PMID:9284050

  2. Regulation of DNA synthesis and the cell cycle in human prostate cancer cells and lymphocytes by ovine uterine serpin

    Directory of Open Access Journals (Sweden)

    Hansen Peter J

    2008-01-01

    Full Text Available Abstract Background Uterine serpins are members of the serine proteinase inhibitor superfamily. Like some other serpins, these proteins do not appear to be functional proteinase inhibitors. The most studied member of the group, ovine uterine serpin (OvUS, inhibits proliferation of several cell types including activated lymphocytes, bovine preimplantation embryos, and cell lines for lymphoma, canine primary osteosarcoma and human prostate cancer (PC-3 cells. The goal for the present study was to evaluate the mechanism by which OvUS inhibits cell proliferation. In particular, it was tested whether inhibition of DNA synthesis in PC-3 cells involves cytotoxic actions of OvUS or the induction of apoptosis. The effect of OvUS in the production of the autocrine and angiogenic cytokine interleukin (IL-8 by PC-3 cells was also determined. Finally, it was tested whether OvUS blocks specific steps in the cell cycle using both PC-3 cells and lymphocytes. Results Recombinant OvUS blocked proliferation of PC-3 cells at concentrations as low as 8 μg/ml as determined by measurements of [3H]thymidine incorporation or ATP content per well. Treatment of PC-3 cells with OvUS did not cause cytotoxicity or apoptosis or alter interleukin-8 secretion into medium. Results from flow cytometry experiments showed that OvUS blocked the entry of PC-3 cells into S phase and the exit from G2/M phase. In addition, OvUS blocked entry of lymphocytes into S phase following activation of proliferation with phytohemagglutinin. Conclusion Results indicate that OvUS acts to block cell proliferation through disruption of the cell cycle dynamics rather than induction of cytotoxicity or apoptosis. The finding that OvUS can regulate cell proliferation makes this one of only a few serpins that function to inhibit cell growth.

  3. Prostatic acid phosphatase is the main acid phosphatase with 5'-ectonucleotidase activity in the male mouse saliva and regulates salivation.

    Science.gov (United States)

    Araujo, César L; Quintero, Ileana B; Kipar, Anja; Herrala, Annakaisa M; Pulkka, Anitta E; Saarinen, Lilli; Hautaniemi, Sampsa; Vihko, Pirkko

    2014-06-01

    We have previously shown that in addition to the well-known secreted isoform of prostatic acid phosphatase (sPAP), a transmembrane isoform exists (TMPAP) that interacts with snapin (a SNARE-associated protein) and regulates the endo-/exocytic pathways. We have also shown that PAP has 5'-ectonucleotidase and thiamine monophosphatase activity and elicits antinociceptive effects in mouse models of chronic inflammatory and neuropathic pain. Therefore, to determine the physiological role of PAP in a typical exocrine organ, we studied the submandibular salivary gland (SMG) of PAP(-/-) and wild-type C57BL/6J mice by microarray analyses, microRNA sequencing, activity tests, immunohistochemistry, and biochemical and physiological analyses of saliva. We show that PAP is the main acid phosphatase in the wild-type male mouse saliva, accounting for 50% of the total acid phosphatase activity, and that it is expressed only in the granular convoluted tubules of the SMGs, where it is the only 5'-ectonucleotidase. The lack of PAP in male PAP(-/-) mice was associated with a significant increase in the salivation volume under secretagogue stimulation, overexpression of genes related to cell proliferation (Mki67, Aurkb, Birc5) and immune response (Irf7, Cxcl9, Ccl3, Fpr2), and upregulation of miR-146a in SMGs. An increased and sustained acinar cell proliferation was detected without signs of glandular hyperplasia. Our results indicate that in PAP(-/-) mice, SMG homeostasis is maintained by an innate immune response. Additionally, we suggest that in male mice, PAP via its 5'-ectonucleotidase activity and production of adenosine can elicit analgesic effects when animals lick their wounds. PMID:24717577

  4. Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection with Chlamydia Species▿

    OpenAIRE

    Zhou, Xiaohui; Chen, Qiangwei; Moore, Jessica; Kolls, Jay K.; Halperin, Scott; Wang, Jun

    2009-01-01

    The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17...

  5. EphA receptors regulate prostate cancer cell dissemination through Vav2–RhoA mediated cell–cell repulsion

    Directory of Open Access Journals (Sweden)

    Jennifer Batson

    2014-05-01

    Full Text Available Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion when they contact one another. The impact of these ‘social’ interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here we show that EphA receptors regulate prostate cancer cell dissemination in a 2D dispersal assay and in a 3D cancer cell spheroid assay. We show that EphA receptors signal via the exchange factor Vav2 to activate RhoA and that both Vav2 and RhoA are required for prostate cancer cell–cell repulsion. Furthermore, we find that in EphA2/EphA4, Vav2 or RhoA siRNA-treated cells, contact repulsion can be restored by partial microtubule destabilisation. We propose that EphA–Vav2–RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local invasion away from the primary tumour.

  6. Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases.

    Science.gov (United States)

    Tertil, Magdalena; Golda, Slawomir; Skrzypek, Klaudia; Florczyk, Urszula; Weglarczyk, Kazimierz; Kotlinowski, Jerzy; Maleszewska, Monika; Czauderna, Szymon; Pichon, Chantal; Kieda, Claudine; Jozkowicz, Alicja; Dulak, Jozef

    2015-12-01

    Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic malignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2- and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metalloproteinases and inflammatory cytokine interleukin-1β, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound transcriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis. PMID:26393425

  7. Salvianolic Acid A Protects the Peripheral Nerve Function in Diabetic Rats through Regulation of the AMPK-PGC1α-Sirt3 Axis

    Directory of Open Access Journals (Sweden)

    Guanhua Du

    2012-09-01

    Full Text Available Salvianolic acid A (SalA is one of the main efficacious, water-soluble constituents of Salvia miltiorrhiza Bunge. This study investigated the protective effects of SalA on peripheral nerve in diabetic rats. Administration of SalA (0.3, 1 and 3 mg/kg, ig was started from the 5th week after strepotozotocin (STZ60 mg/kg intraperitoneal injection and continued for 8 weeks. Paw withdrawal mechanical threshold (PWMT and motor nerve conduction velocity (MNCV were used to assess peripheral nerve function. The western blot methods were employed to test the expression levels of serine-threonine liver kinase B1 (LKB1, AMP-activated protein kinase (AMPK, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α, silent information regulator protein3 (sirtuin 3/Sirt3 and neuronal nitric oxide synthase (nNOS in sciatic nerve. Results showed that SalA administration could increase PWMT and MNCV in diabetic rats; reduce the deterioration of sciatic nerve pathology; increase AMPK phosphorylation level, up-regulate PGC-1α, Sirt3 and nNOS expression, but had no influence on LKB1. These results suggest that SalA has protective effects against diabetic neuropathy. The beneficial effects of SalA on peripheral nerve function in diabetic rats might be attributed to improvements in glucose metabolism through regulation of the AMPK-PGC1α-Sirt3 axis.

  8. Mesenchymal stem cells regulate mechanical properties of human degenerated nucleus pulposus cells through SDF-1/CXCR4/AKT axis.

    Science.gov (United States)

    Liu, Ming-Han; Bian, Bai-Shi-Jiao; Cui, Xiang; Liu, Lan-Tao; Liu, Huan; Huang, Bo; Cui, You-Hong; Bian, Xiu-Wu; Zhou, Yue

    2016-08-01

    Transplantation of mesenchymal stem cells (MSCs) into the degenerated intervertebral disc (IVD) has shown promise for decelerating or arresting IVD degeneration. Cellular mechanical properties play crucial roles in regulating cell-matrix interactions, potentially reflecting specific changes that occur based on cellular phenotype and behavior. However, the effect of co-culturing of MSCs with nucleus pulposus cells (NPCs) on the mechanical properties of NPCs remains unknown. In our study, we demonstrated that co-culture of degenerated NPCs with MSCs resulted in significantly decreased mechanical moduli (elastic modulus, relaxed modulus, and instantaneous modulus) and increased biological activity (proliferation and expression of matrix genes) in degenerated NPCs, but not normal NPCs. SDF-1, CXCR4 ligand, was highly expressed in MSCs when co-cultured with degenerated NPCs. Inhibition of SDF-1 using CXCR4 antagonist AMD3100 or knocking-down CXCR4 in degenerated NPCs abolished the MSCs-induced decrease in the mechanical moduli and increased biological activity of degenerated NPCs, suggesting a crucial role for SDF-1/CXCR4 signaling. AKT and FAK inhibition attenuated the MSCs- or SDF-1-induced decrease in the mechanical moduli of degenerated NPCs. In conclusion, it was demonstrated in vitro that MSCs regulate the mechanical properties of degenerated NPCs through SDF-1/CXCR4/AKT signaling. These findings highlight a possible mechanical mechanism for MSCs-induced modulation with degenerated NPCs, which may be applicable to MSCs-based therapy for disc degeneration. PMID:27163878

  9. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.

    Science.gov (United States)

    Purushottamachar, Puranik; Godbole, Abhijit M; Gediya, Lalji K; Martin, Marlena S; Vasaitis, Tadas S; Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Ates-Alagoz, Zeynep; Njar, Vincent C O

    2013-06-27

    As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer. PMID:23713567

  10. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    International Nuclear Information System (INIS)

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin

  11. Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

    International Nuclear Information System (INIS)

    The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development

  12. Prostate brachytherapy

    Science.gov (United States)

    Implant therapy - prostate cancer; Radioactive seed placement; Internal radiation therapy - prostate; High dose radiation (HDR) ... Brachytherapy takes 30 minutes or more, depending on the type of therapy you have. Before the procedure, ...

  13. Prostate Cancer

    Science.gov (United States)

    ... man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  14. Prostate Cancer

    Science.gov (United States)

    ... a man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... men younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  15. Prostate biopsy

    Science.gov (United States)

    ... from the prostate through the scope. Perineal - through perineum (the skin between the anus and the scrotum). ... pain. A small cut is made in the perineum. A needle is inserted to collect prostate tissue.

  16. Prostatitis - bacterial

    Science.gov (United States)

    Any bacteria that can cause a urinary tract infection can cause acute bacterial prostatitis. Infections spread through sexual contact can cause prostatitis. These include chlamydia and gonorrhea . Sexually transmitted ...

  17. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.

    Science.gov (United States)

    Wang, Xiaowei; Shaw, Dana K; Hammond, Holly L; Sutterwala, Fayyaz S; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J; Bonventre, Joseph V; Velayutham, Thangam S; Evans, Sean M; Rodino, Kyle G; VieBrock, Lauren; Scanlon, Karen M; Carbonetti, Nicholas H; Carlyon, Jason A; Miao, Edward A; McBride, Jere W; Kotsyfakis, Michail; Pedra, Joao H F

    2016-08-01

    Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID:27482714

  18. ACE2/Ang 1-7 axis: A critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity.

    Science.gov (United States)

    Patel, Vaibhav B; Basu, Ratnadeep; Oudit, Gavin Y

    2016-01-01

    Obesity is characterized by an excessive fat accumulation in adipose tissues leading to weight gain and is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; activated RAS and angiotensin (Ang) II production results in worsening of cardiovascular diseases and angiotensin converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. ACE2 is expressed in the adipocytes and its expression is upregulated in response to high fat diet induced obesity in mice. Loss of ACE2 results in heart failure with preserved ejection fraction which is mediated in part by epicardial adipose tissue inflammation. Angiotensin 1-7 reduces the obesity associated cardiac dysfunction predominantly via its role in adiponectin expression and attenuation of epicardial adipose tissue inflammation. Human heart disease is also linked with inflammed epicardial adipose tissue. Here, we discuss the important interpretation of the novel of ACE2/Ang 1-7 pathway in obesity associated cardiac dysfunction. PMID:27617176

  19. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

    Science.gov (United States)

    Wang, Xiaowei; Shaw, Dana K.; Hammond, Holly L.; Sutterwala, Fayyaz S.; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J.; Bonventre, Joseph V.; Velayutham, Thangam S.; Evans, Sean M.; Rodino, Kyle G.; VieBrock, Lauren; Scanlon, Karen M.; Carbonetti, Nicholas H.; Carlyon, Jason A.; Miao, Edward A.; McBride, Jere W.; Kotsyfakis, Michail

    2016-01-01

    Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID:27482714

  20. Chronic prostatitis

    OpenAIRE

    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian

    2008-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  1. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

    DEFF Research Database (Denmark)

    Jiang, Nan; Hjorth-Jensen, Kim; Hekmat, Omid;

    2015-01-01

    Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic app...

  2. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    DEFF Research Database (Denmark)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb;

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with c...

  3. Fibroblast growth factor-2 up-regulates the expression of nestin through the Ras–Raf–ERK–Sp1 signaling axis in C6 glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Kai-Wei [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Yuan-Li [Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan (China); Wong, Zong-Ruei; Su, Peng-Han [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Bu-Miin [Department of Cell Biology and Anatomy, National Cheng-Kung University, Tainan 701, Taiwan (China); Ju, Tsai-Kai [Instrumentation Center, National Taiwan University, Taipei 106, Taiwan (China); Technology Commons, College of Life Science, National Taiwan University, Taipei 106, Taiwan (China); Yang, Hsi-Yuan, E-mail: hyhy@ntu.edu.tw [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China)

    2013-05-17

    Highlights: •Nestin expression in C6 glioma cells is induced by FGF-2. •Nestin expression is induced by FGF-2 via de novo RNA and protein synthesis. •The FGFR inhibitor SU5402 blocks the FGF-2-induced nestin expression. •The mRNA of FGFR1 and 3 are detected in C6 glioma cells. •Ras–Raf–ERK–Sp1 signaling pathway is responsibe for FGF-2-induced nestin expression. -- Abstract: Nestin is a 240-kDa intermediate filament protein expressed mainly in neural and myogenic stem cells. Although a substantial number of studies have focused on the expression of nestin during development of the central nervous system, little is known about the factors that induce and regulate its expression. Fibroblast growth factor-2 (FGF-2) is an effective mitogen and stimulates the proliferation and differentiation of a subset of nestin-expressing cells, including neural progenitor cells, glial precursor cells, and smooth muscle cells. To assess whether FGF-2 is a potent factor that induces the expression of nestin, C6 glioma cells were used. The results showed that nestin expression was up-regulated by FGF-2 via de novo RNA and protein synthesis. Our RT-PCR results showed that C6 glioma cells express FGFR1/3, and FGFRs is required for FGF-2-induced nestin expression. Further signaling analysis also revealed that FGF-2-induced nestin expression is mediated through FGFR–MAPK–ERK signaling axis and the transcriptional factor Sp1. These findings provide new insight into the regulation of nestin in glial system and enable the further studies on the function of nestin in glial cells.

  4. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation

    International Nuclear Information System (INIS)

    Although most of pharmacological therapies for cancer utilize the apoptotic machinery of the cells, the available anti-cancer drugs are limited due to the ability of prostate cancer cells to escape from the anti-cancer drug-induced apoptosis. A human prostate cancer cell line PC3 is resistant to camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of sphingosine kinase (SPHK) and sphingosine 1-phosphate (S1P) receptor in CPT-resistant PC3 and -sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1, and also elevated expression of S1P receptors, S1P1 and S1P3, as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA and inhibition of S1P receptor signaling by pertussis toxin in PC3 cells induced significant inhibition of cell growth, suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/S1P signaling by induction of both SPHK1 enzyme and S1P1/S1P3 receptors. These findings strongly suggest that high expression and up-regulation of SPHK1 and S1P receptors protect PC3 cells from the apoptosis induced by CPT

  5. Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer.

    Science.gov (United States)

    Das, Trinath P; Suman, Suman; Papu John, A M Sashi; Pal, Deeksha; Edwards, Angelena; Alatassi, Houda; Ankem, Murali K; Damodaran, Chendil

    2016-07-28

    The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression was seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the proliferative function of AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of CaP cells. In addition, AKT over-expressed tumors exhibit aggressive growth when compared to control vector in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors as compared to control tumors. Finally, we examined the expression pattern of AKT and DAPK3 in human CaP specimens - the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be a therapeutic target for CaP. PMID:27126362

  6. Progress against Prostate Cancer

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  7. Learning about Prostate Cancer

    Science.gov (United States)

    ... of Information on Prostate Cancer What is prostate cancer? Prostate cancer is the most common cancer in American ... of page Additional Resources of Information on Prostate Cancer Prostate Cancer [nlm.nih.gov] From Medline Plus Medical ...

  8. Stages of Prostate Cancer

    Science.gov (United States)

    ... Renal Cell) Cancer Leukemia Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ... Cancer Treatment Prostate Cancer Prevention Genetics of Prostate Cancer Prostate Cancer Screening Research Prostate Cancer Treatment (PDQ®)–Patient ...

  9. The Role of Estrogen Receptor β in Prostate Cancer

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the re...

  10. The role of Estrogen Receptor Beta in Prostate Cancer.

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of prostate gland, estrogen receptor beta (ERβ) is involved contributive in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. Nowadays, ERß is a promising target as an anticancer therapy and prevention for prostate cancer....

  11. Androgen-targeted therapy induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention

    Directory of Open Access Journals (Sweden)

    Mannan eNouri

    2014-12-01

    Full Text Available Androgens regulate biological pathways to promote proliferation, differentiation and survival of benign and malignant prostate tissue. Androgen receptor targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or androgen receptor function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation has been shown to activate both epithelial-to-mesenchymal transition (EMT and neuroendocrine transdifferentiation programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy in multiple human cancer types. Neuroendocrine transdifferentiation in prostate cancer is associated with resistance to therapy, visceral metastasis and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK and aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

  12. Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

    Science.gov (United States)

    Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

    2016-06-01

    Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P diabetic rats. Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P diabetic rats, an effect which was significantly increased after administration of taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis. PMID:27089006

  13. A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability.

    Science.gov (United States)

    Choi, Hye-Jeong; Kwon, Seongran; Kim, Dae-Won

    2016-09-01

    While Nkx3.2/Bapx1 promotes chondrogenic differentiation and plays a role in maintaining chondrocyte viability and suppressing chondrocyte hypertrophy, the regulatory mechanisms of Nkx3.2 remain poorly understood. Here we show that p300- and HDAC9-induced Nkx3.2 acetylation and de-acetylation, respectively, play critical roles in controlling Nkx3.2 protein stability. In addition, we also found that HDAC9-dependent de-acetylation of Nkx3.2 triggers PIASy-mediated sumoylation and subsequent RNF4-mediated SUMO-targeted ubiquitination. Furthermore, we demonstrate that Nkx3.2 regulation by HDAC9 can be linked to the management of chondrocyte survival and hypertrophic maturation during cartilage development. Finally, our results together reveal a novel mechanism of protein stability control involving complex interplay between acetylation, de-acetylation, sumoylation, and ubiquitination, and suggest that this post-translational modification of Nkx3.2 employing HDAC9-PIASy-RNF4 axis plays a crucial role in controlling chondrocyte viability and hypertrophic maturation during skeletal development in vertebrates. PMID:27312341

  14. Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-integrin-RhoA signaling axis.

    Science.gov (United States)

    Deevi, Ravi Kiran; Cox, Orla T; O'Connor, Rosemary

    2014-05-01

    PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB) and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT). PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (β1) integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R) and Receptor of activated protein kinase C 1 (RACK1), which scaffolds IGF-1R to β1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK) and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase) activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK) was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the β1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium. PMID:24863845

  15. Essential Function for PDLIM2 in Cell Polarization in Three-Dimensional Cultures by Feedback Regulation of the β1-Integrin–RhoA Signaling Axis

    Directory of Open Access Journals (Sweden)

    Ravi Kiran Deevi

    2014-05-01

    Full Text Available PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT. PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (β1 integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R and Receptor of activated protein kinase C 1 (RACK1, which scaffolds IGF-1R to β1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the β1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium.

  16. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Ming-De Yan

    2015-09-01

    Full Text Available Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC. Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1, a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9, by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

  17. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    Science.gov (United States)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B.; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Zheng, Wei; Signorello, Lisa B.; Blot, William J.; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, J. Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J.; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes L.; Freedman, Matthew L.; Haiman, Christopher A.; Pasaniuc, Bogdan

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. PMID:27052111

  18. Inhibitory effect of triptolide on lymph node metastasis in patients with non-Hodgkin lymphoma by regulating SDF-1/CXCR4 axis in vitro

    Institute of Scientific and Technical Information of China (English)

    Chun ZHANG; Guo-hui CUI; Fang LIU; Qiu-ling WU; Yan CHEN

    2006-01-01

    Aim: To investigate the antiproliferative effect of triptolide on B-NHL cell line Raji cells, to study its effect on lymph node metastasis in patients with non-Hodgkin's lymphoma (NHL) in vitro, and to explore the underlying mechanism regulating SDF-1/CXCR4 axis. Methods: The effects of triptolide on the growth of Raji cells were studied by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. The effects of triptolide on SDF-1 mRNA expression in lymph node stromal cells from patients with NHL were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The effects of triptolide on CXCR4 expression on lymphoma cells freshly isolated from the lymph nodes of these patients were studied by flow cytometric analysis. Chemotaxis assays were performed to observe the effects of triptolide on migration of primary lymphoma cells towards recombinant human SDF-la (rhSDF-1α) or cultured lymph node stromal cells in vitro. Results: Triptolide inhibited the proliferation of B-NHL cell line Raji cells in a dose- and time-dependent manner with a 24-h IC50 value of 43.06 nmol/L and a 36-h IC50 value of 25.08 nmol/L. The expression of SDF-la mRNA in lymph node stromal cells obtained from patients with NHL was decreased after treatment by triptolide at concentrations of 25 and 50 nmol/L for 24 h. Flow cytometry analysis showed that the CXCR4 expression on primary lymphoma cells were downregulated gradually in a dose-dependent manner following triptolide treatment. Chemotaxis assays revealed that the migration of freshly isolated lymphoma cells towards either rhSDF-1 or cultured lymph node stromal cells was markedly inhibited by the addition of triptolide in vitro, and the inhibition was dose-dependent. Conclusion: Triptolide can inhibit the proliferation of B-NHL cell line Raji cells. Moreover, triptolide is able to inhibit the migration of lymphoma cells via lymph nodes in vitro. The potential antitumor mechanisms of triptolide are related to the

  19. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

    Directory of Open Access Journals (Sweden)

    Poyil Pratheeshkumar

    Full Text Available Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

  20. Prostate cancer

    International Nuclear Information System (INIS)

    This work is about diagnosis, treatment and monitoring of prostate cancer. The techniques used are: transrectal ultrasound, laparascopy, bone scan, chest x-ray, radiography, chemoterapy and radiotherapy

  1. AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis.

    Science.gov (United States)

    Mangalam, Ashutosh K; Rattan, Ramandeep; Suhail, Hamid; Singh, Jaspreet; Hoda, Md Nasrul; Deshpande, Mandar; Fulzele, Sadanand; Denic, Alexander; Shridhar, Viji; Kumar, Ashok; Viollet, Benoit; Rodriguez, Moses; Giri, Shailendra

    2016-08-01

    The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood-brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10(low)IL-23/IL-1β/IL-6(high)), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35-55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35-55-primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4(+) T cells were due to an autocrine effect of IL-1β/IL-23-mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype-Th17 axis in an animal model of multiple sclerosis. PMID:27354217

  2. Glypican1/2/4/6 and sulfated glycosaminoglycans regulate the patterning of the primary body axis in the cnidarian Nematostella vectensis.

    Science.gov (United States)

    Bause, Markus; van der Horst, Roddy; Rentzsch, Fabian

    2016-06-01

    Glypicans are members of the heparan sulfate (HS) subfamily of proteoglycans that can function in cell adhesion, cell crosstalk and as modulators of the major developmental signalling pathways in bilaterians. The evolutionary origin of these multiple functions is not well understood. In this study we investigate the role of glypicans in the embryonic and larval development of the sea anemone Nematostella vectensis, a member of the non-bilaterian clade Cnidaria. Nematostella has two glypican (gpc) genes that are expressed in mutually exclusive ectodermal domains, NvGpc1/2/4/6 in a broad aboral domain, and NvGpc3/5 in narrow oral territory. The endosulfatase NvSulf (an extracellular modifier of HS chains) is expressed in a broad oral domain, partially overlapping with both glypicans. Morpholino-mediated knockdown of NvGpc1/2/4/6 leads to an expansion of the expression domains of aboral marker genes and a reduction of oral markers at gastrula stage, strikingly similar to knockdown of the Wnt receptor NvFrizzled5/8. We further show that treatment with sodium chlorate, an inhibitor of glycosaminoglycan (GAG) sulfation, phenocopies knockdown of NvGpc1/2/4/6 at gastrula stage. At planula stage, knockdown of NvGpc1/2/4/6 and sodium chlorate treatment result in alterations in aboral marker gene expression that suggest additional roles in the fine-tuning of patterning within the aboral domain. These results reveal a role for NvGpc1/2/4/6 and sulfated GAGs in the patterning of the primary body axis in Nematostella and suggest an ancient function in regulating Frizzled-mediated Wnt signalling. PMID:27090806

  3. TGF-β regulates DNA methyltransferase expression in prostate cancer, correlates with aggressive capabilities, and predicts disease recurrence.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    Full Text Available BACKGROUND: DNA methyltransferase (DNMT is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs. This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP. The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy. METHODOLOGY/PRINCIPAL FINDINGS: We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer. CONCLUSIONS AND SIGNIFICANCE: Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease

  4. Biomarkers in Prostate Cancer Epidemiology

    Directory of Open Access Journals (Sweden)

    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  5. The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation.

    Science.gov (United States)

    Shinderman-Maman, E; Cohen, K; Weingarten, C; Nabriski, D; Twito, O; Baraf, L; Hercbergs, A; Davis, P J; Werner, H; Ellis, M; Ashur-Fabian, O

    2016-04-14

    Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical

  6. Inflammatory Genetic Markers of Prostate Cancer Risk

    International Nuclear Information System (INIS)

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk

  7. Down-regulation of phosphoglucomutase 3 mediates sulforaphane-induced cell death in LNCaP prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Lee Hyo-Jeong

    2010-12-01

    Full Text Available Abstract Background Sulforaphane (SFN is an isothiocyanate found in cruciferous vegetables that exerts anti-oxidant, anti-inflammatory, anti-cancer and radio-sensitizing activities. Nonetheless, the mechanism responsible for SFN-induced cell death is not fully understood. In the present study, anti-cancer mechanism of SFN was elucidated in LNCaP prostate cancer cells. Results SFN exerted cytotoxicity and increased TUNEL positive cells in a concentration-dependent manner in LNCaP cells. Proteomics study revealed that levels of nine proteins including tubulin β-2, phosphoglucomutase-3 (PGM3, melanoma-derived leucine zipper containing extra-nuclear factor, activin A type I receptor precursor, smoothelin-A, KIA0073, hypothetical protein LOC57691 and two unnamed proteins were changed over 8 folds in SFN treated LNCaP cells compared to untreated control. We have further confirmed that SFN reduced PGM3 expression with western blotting and showed that PGM3 siRNA enhanced cytotoxicity demonstrated by cell morphology and TUNEL assays in LNCaP cells. Conclusion Taken together, these findings suggest that PGM3 plays a role in mediating SFN-induced cell death in LNCaP cells, and is a potential molecular therapeutic target for prostate cancer.

  8. Prostate Cancer (Radiation Therapy)

    Science.gov (United States)

    ... Physician Resources Professions Site Index A-Z Prostate Cancer Treatment Prostate cancer overview? What are my treatment options? What ... any new developments in treating my disease? Prostate cancer overview Prostate cancer is the most common form of cancer ...

  9. What is Prostate Cancer?

    Science.gov (United States)

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » What is prostate cancer? Share ... how cancers start and spread, see What Is Cancer? Prostate cancer begins when cells in the prostate gland ...

  10. Cryotherapy for prostate cancer

    Science.gov (United States)

    Cryosurgery-prostate cancer; Cryoablation-prostate cancer ... Prostate Cancer. American Cancer Society. www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-cryosurgery. Accessed August 31, 2015. Horwich ...

  11. Oridonin Up-regulates Expression of P21 and Induces Autophagy and Apoptosis in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xiang Li, Xiang Li, Jiaxiong Wang, Zaiyuan Ye, Ji-Cheng Li

    2012-01-01

    Full Text Available Background: Oridonin (ORI could inhibit the proliferation and induce apoptosis in various cancer cell lines. However, the mechanism is not fully understood.Methods: Human prostate cancer (HPC cells were cultured in vitro and cell viability was detected by the CCK-8 assay. The ultrastructure changes were observed under transmission electron microscope (TEM. Chemical staining with acridine orange (AO, MDC or DAPI was used to detect acidic vesicular organelles (AVOs and alternation of DNA. Expression of LC3 and P21 was detected by Western Blot. Apoptotic rates and cell cycle arrest were detected by FACS.Results: Our study demonstrated that after ORI treatment, the proliferations of human prostate cancer (HPC cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell cycle arrest at the G2/M phase. A large number of autophagosomes with double-membrane structure and acidic vesicular organelles (AVOs were detected in the cytoplasm of HPC cells treated with ORI for 24 hours. ORI resulted in the conversion of LC3-I to LC3-II and recruitment of LC3-II to the autophagosomal membranes. Autophagy inhibitor 3-methyladenine (3-MA reduced AVOs formation and inhibited LC3-I to LC3-II conversion. At 48 h, DNA fragmentation, chromatin condensation and disappearance of surface microvilli were detected in ORI-treated cells. ORI induced a significant increase in the number of apoptotic cells (PC-3: 5.4% to 27.0%, LNCaP: 5.3% to 31.0%. Promoting autophagy by nutrient starvation increased cell viability, while inhibition of autophagy by 3-MA promoted cell death. The expression of P21 was increased by ORI, which could be completely reversed by the inhibition of autophagy.Conclusions: Our findings indicated that autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis. Our results provide an experimental basis for understand

  12. Prostatic melanosis

    Directory of Open Access Journals (Sweden)

    Kemal DENİZ

    2007-09-01

    Full Text Available Prostatic melanosis is a rare lesion that is characterized by melanin-containing spindle cells mainly located in the stroma of the prostate gland. This lesion is certainly benign and not a precursor of malignant melanoma. However, differential diagnosis of melanosis with primary and metastatic malignant melanoma is extremely important because of the different biological nature and clinical behavior of these two entities. Recognition of the spectrum of pigmented lesions in the prostate gland is essential to take into consideration of the diagnosis of melanocytic lesions.In this paper, a case of melanosis

  13. Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells

    Directory of Open Access Journals (Sweden)

    Li Wen-Cheng

    2010-11-01

    Full Text Available Abstract Background Previously we reported extensive gene expression reprogramming during epithelial to mesenchymal transition (EMT of primary prostate cells. Here we investigated the hypothesis that specific histone and DNA methylations are involved in coordination of gene expression during EMT. Results Genome-wide profiling of histone methylations (H3K4me3 and H3K27me3 and DNA methylation (DNAMe was applied to three cell lines at different stages of a stepwise prostate cell model involving EMT and subsequent accumulation of malignant features. Integrated analyses of epigenetic promoter modifications and gene expression changes revealed strong correlations between the dynamic changes of histone methylations and gene expression. DNA methylation was weaker associated with global gene repression, but strongly correlated to gene silencing when genes co-modified by H3K4me3 were excluded. For genes labeled with multiple epigenetic marks in their promoters, the level of transcription was associated with the net signal intensity of the activating mark H3K4me3 minus the repressive marks H3K27me3 or DNAMe, indicating that the effect on gene expression of bivalent marks (H3K4/K27me3 or H3K4me3/DNAMe depends on relative modification intensities. Sets of genes, including epithelial cell junction and EMT associated fibroblast growth factor receptor genes, showed corresponding changes concerning epigenetic modifications and gene expression during EMT. Conclusions This work presents the first blueprint of epigenetic modifications in an epithelial cell line and the progeny that underwent EMT and shows that specific histone methylations are extensively involved in gene expression reprogramming during EMT and subsequent accumulation of malignant features. The observation that transcription activity of bivalently marked genes depends on the relative labeling intensity of individual marks provides a new view of quantitative regulation of epigenetic modification.

  14. Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha.

    Science.gov (United States)

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; De Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V; Filippini, Antonio; Riccioli, Anna

    2010-07-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1 alpha and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1 alpha. However, the transfection of I.3 isoform of hif-1 alpha in LNCaP cells allows poly(I:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1 alpha expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists. PMID:20651983

  15. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α1

    Science.gov (United States)

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; De Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V; Filippini, Antonio; Riccioli, Anna

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of I.3 isoform of hif-1α in LNCaP cells allows poly(I:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists. PMID:20651983

  16. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α

    Directory of Open Access Journals (Sweden)

    Alessio Paone

    2010-07-01

    Full Text Available Toll-like receptors (TLRs recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-induciblefactor 1 (HIF-1regulates several cellular processes, includingapoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific 1.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF. Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of 1.3 isoform of hif-1α in LNCaP cells allows poly(I:CI-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists.

  17. Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence.

    Science.gov (United States)

    Sunkel, Benjamin; Wu, Dayong; Chen, Zhong; Wang, Chiou-Miin; Liu, Xiangtao; Ye, Zhenqing; Horning, Aaron M; Liu, Joseph; Mahalingam, Devalingam; Lopez-Nicora, Horacio; Lin, Chun-Lin; Goodfellow, Paul J; Clinton, Steven K; Jin, Victor X; Chen, Chun-Liang; Huang, Tim H-M; Wang, Qianben

    2016-05-19

    Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes. PMID:26743006

  18. Prostatitis - acute

    Science.gov (United States)

    ... bladder, such as alcohol, caffeinated foods and drinks, citrus juices, and hot or spicy foods. Drink more ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Diseases Browse the Encyclopedia A.D. ...

  19. Prostate cancer

    DEFF Research Database (Denmark)

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  20. Prostate cancer

    DEFF Research Database (Denmark)

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data.......To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  1. [Novel treatment for prostate cancer targeting prostaglandins].

    Science.gov (United States)

    Terada, Naoki; Inoue, Takahiro; Kamba, Tomomi; Ogawa, Osamu

    2014-12-01

    PGE2 is highly expressed in the prostate, associating with prostate cancer progression. Targeting downstream signaling pathways of PGE2 may represent an attractive new strategy for the treatment of prostate cancer. We have established a novel prostate cancer xenograft model, KUCaP-2. The expression of EP4, one of PGE2 receptors, was significantly up-regulated during the development of castration resistance. A specific EP4 antagonist, ONO-AE3-208, decelerated castration-resistant growth of KUCaP-2 tumors in vivo. Moreover, ONO-AE3-208 could in vitro inhibit the cell invasion and in vivo suppress the bone metastasis of prostate cancer cells. These results indicated that EP4 is a novel target for the treatment of metastatic castration resistant prostate cancer. PMID:25518348

  2. The genomic landscape of prostate cancer

    Directory of Open Access Journals (Sweden)

    Sylvan eBaca

    2012-05-01

    Full Text Available Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.

  3. ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

    International Nuclear Information System (INIS)

    Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production. We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways. Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation. We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression

  4. Autonomous and nonautonomous regulation of axis formation by antagonistic signaling via 7-span cAMP receptors and GSK3 in Dictyostelium

    OpenAIRE

    Ginsburg, Gail T.; Alan R. Kimmel

    1997-01-01

    Early during Dictyostelium development a fundamental cell-fate decision establishes the anteroposterior (prestalk/prespore) axis. Signaling via the 7-transmembrane cAMP receptor CAR4 is essential for creating and maintaining a normal pattern; car4-null alleles have decreased levels of prestalk-specific mRNAs but enhanced expression of prespore genes. car4− cells produce all of the signals required for prestalk differentiation but lack an extracellular factor necessary for prespore differentia...

  5. BMP and retinoic acid regulate anterior–posterior patterning of the non-axial mesoderm across the dorsal–ventral axis

    Science.gov (United States)

    Naylor, Richard W.; Skvarca, Lauren Brilli; Thisse, Christine; Thisse, Bernard; Hukriede, Neil A.; Davidson, Alan J.

    2016-01-01

    Despite the fundamental importance of patterning along the dorsal–ventral (DV) and anterior–posterior (AP) axes during embryogenesis, uncertainty exists in the orientation of these axes for the mesoderm. Here we examine the origin and formation of the zebrafish kidney, a ventrolateral mesoderm derivative, and show that AP patterning of the non-axial mesoderm occurs across the classic gastrula stage DV axis while DV patterning aligns along the animal–vegetal pole. We find that BMP signalling acts early to establish broad anterior and posterior territories in the non-axial mesoderm while retinoic acid (RA) functions later, but also across the classic DV axis. Our data support a model in which RA on the dorsal side of the embryo induces anterior kidney fates while posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1. This work clarifies our understanding of vertebrate axis orientation and establishes a new paradigm for how the kidney and other mesodermal derivatives arise during embryogenesis. PMID:27406002

  6. Exophytic benign prostatic hyperplasia.

    Science.gov (United States)

    Blaschko, Sarah D; Eisenberg, Michael L

    2011-08-01

    A 60-year-old man had incidental finding of a multilobular 8 × 7 × 7-cm mass identified posterior to the urinary bladder in continuity with the prostate. The man's prostate-specific antigen was 1.87, and he denied any lower urinary tract symptoms. A transrectal ultrasound-guided biopsy demonstrated benign prostatic tissue. A computed tomography-guided needle aspiration demonstrated a benign epithelium-lined cyst, likely prostatic in origin. Benign prostatic hyperplasia is a proliferation of prostatic epithelial and stromal cells. Although prostatic hyperplasia is usually restricted to the prostate gland, hyperplastic nodules occasionally protrude outside the prostate and rarely form exophytic pelvic masses. PMID:20869104

  7. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage

    Institute of Scientific and Technical Information of China (English)

    Yuting Lin; Junichi Fukuchi; Richard A Hiipakka; John M Kokontis; Jialing Xiang

    2007-01-01

    Bcl-2 is an anti-apoptotic oncoprotein and its protein levels are inversely correlated with prognosis in many cancers.However, the role of Bcl-2 in the progression of prostate cancer is not clear. Here we report that Bcl-2 is required for the progression of LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. The mRNA and protein levels of Bcl-2 are significantly increased in androgen-independent prostate cancer cells, shRNA-mediated gene silencing of Bcl-2 in androgen-independent prostate cancer cells promotes UV-induced apoptosis and suppresses the growth of prostate tumors in vivo. Growing androgen-dependent cells under androgen-deprivation conditions results in formation of androgen-independent colonies; and the transition from androgen-dependent to androgen-independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA. Thus, our results demonstrate that Bcl-2 is not only critical for the survival of androgen-independent prostate cancer cells, but is also required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage.

  8. Risk factors for prostatic inflammation extent and infection in benign prostatic hyperplasia

    Institute of Scientific and Technical Information of China (English)

    Fa-Xian Yi; Qiang Wei; Hong Li; Xiang Li; Ming Shi; Qiang Dong; Yu-Ru Yang

    2006-01-01

    Aim: To investigate the risk factors for prostatic inflammation extent and infection in patients with benign prostatic hyperplasia (BPH) so as to manage prostatic inflammation more efficiently. Methods: Sixty patients with BPH undergoing TURP between September 2005 and December 2005 in West China Hospital of Sichuan University were studied. Prostate fluid (PF) was collected for the measurement of secretory IgA (SIgA) and complement 3 (C3).Prostate tissue were collected for testing bacterial 16S rDNA by real-time PCR, examining SIgA in the tissue and examining the inflammation. The possible clinical and immune risk factors for prostatic inflammation or infection were analyzed by using the logistic regression method. Results: Abnormal white blood cell count in urinalysis, prostatic infection and a high concentration of C3 in PF are the risk factors for prostatic inflammation extent (P = 0.025, 0.034 and 0.035, respectively and odds ratio [OR] = 18.269, 8.284 and 1.508, respectively). Risk factors for prostatic infection include the C3 concentration and the concentration of S IgA in PF (P = 0.003 and 0.013, respectively, and OR= 1.645 and 0.993, respectively). Conclusion: The present study suggests that prostatic inflammation is associated with urinary tract infection, prostatic infection and the activated complement and that prostatic infection is associated with the activated complement and downregulated mucosal immunity in prostates of the patients with BPH. It is also suggested that individual immune regulation should be considered in the treatment of prostatic inflammation and infection of patients with BPH.

  9. Prostate cancer - treatment

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000403.htm Prostate cancer - treatment To use the sharing features on this ... a combination of drugs is recommended. References National Cancer Institute. Prostate cancer treatment (PDQ): Stages of prostate cancer. Updated ...

  10. Cancer of the Prostate

    Science.gov (United States)

    ... will die of this disease. Who Gets This Cancer? Prostate cancer occurs only in men, and it is ... Percent of New Cases by Age Group: Prostate Cancer Prostate cancer is most frequently diagnosed among men aged ...

  11. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... no such thing as one type of prostate cancer. Prostate cancer is really a spectrum of diseases where on ... very benevolent in its behavior. Men will develop prostate cancer and live the rest of their lives -- 20, ...

  12. Localized Prostate Cancer

    Science.gov (United States)

    ... a decision aid for men with clinically localized prostate cancer (available at http://effectivehealthcare.ahrq.gov/prostate_da) ... A Decision Aid for Men With Clinically Localized Prostate Cancer Page 1 of 24 Introduction Men with clinically ...

  13. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... in their lifetime. Age is the most important risk factor in prostate cancer -- the longer a man ... M.D.: There's no such thing as one type of prostate cancer. Prostate cancer is really a ...

  14. Endothelial Cells Can Regulate Smooth Muscle Cells in Contractile Phenotype through the miR-206/ARF6&NCX1/Exosome Axis

    OpenAIRE

    Lin, Xiao; He, Yu; Hou, Xue; Zhang, Zhenming; Wang, Rui; Wu, Qiong

    2016-01-01

    Active interactions between endothelial cells and smooth muscle cells (SMCs) are critical to maintaining the SMC phenotype. Exosomes play an important role in intercellular communication. However, little is known about the mechanisms that regulate endothelial cells and SMCs crosstalk. We aimed to determine the mechanisms underlying the regulation of the SMC phenotype by human umbilical vein endothelial cells (HUVECs) through exosomes. We found that HUVECs overexpressing miR-206 upregulated co...

  15. PIAS1 is a determinant of poor survival and acts as a positive feedback regulator of AR signaling through enhanced AR stabilization in prostate cancer.

    Science.gov (United States)

    Puhr, M; Hoefer, J; Eigentler, A; Dietrich, D; van Leenders, G; Uhl, B; Hoogland, M; Handle, F; Schlick, B; Neuwirt, H; Sailer, V; Kristiansen, G; Klocker, H; Culig, Z

    2016-05-01

    Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies. PMID:26257066

  16. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation.

    Science.gov (United States)

    Yan, L; Zhou, J; Gao, Y; Ghazal, S; Lu, L; Bellone, S; Yang, Y; Liu, N; Zhao, X; Santin, A D; Taylor, H; Huang, Y

    2015-06-01

    The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including Hmga2, c-Myc and Igf2bp3. This H19/let-7-dependent regulation is recapitulated in vivo where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19 via DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities. PMID:25088204

  17. Vitamin D, Sunlight and Prostate Cancer Risk

    Directory of Open Access Journals (Sweden)

    Krishna Vanaja Donkena

    2011-01-01

    Full Text Available Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk. Ultraviolet radiation of the sunlight is the main stimulator for vitamin D production in humans. Vitamin D's antiprostate cancer activities may be involved in the actions through the pathways mediated by vitamin D metabolites, vitamin D metabolizing enzymes, vitamin D receptor (VDR, and VDR-regulated genes. Although laboratory studies including the use of animal models have shown that vitamin D has antiprostate cancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be inconclusive and an intensively studied subject. This review will provide up-to-date information regarding the recent outcomes of laboratory and epidemiology studies on the effects of vitamin D on prostate cancer prevention.

  18. cDNA macroarray for analysis of gene expression profiles in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Early diagnosis and timely treatment are important for improving therapeutic efficiency of prostate cancer. DNA array is a new bio-technology for disease diagnosis. This study was conducted to diagnose prostate cancer with cDNA macroarray and analysis gene expression profiles of some selective genes in prostate cancer.Methods Total RNA was isolated from patients with prostate cancer and from normal people, and poly(A) RNA was further purified. Then it was analyzed for differentially expressed genes in prostate cancer and normal prostate by cDNA macroarray system.Results There were different expressions in the nine prostate-associated specific genes in prostate cancer as compared with normal prostate, in which, 7 were significantly upregulated and 2 were down-regulated.Conclusion As a diagnostic approach at molecular level, the cDNA macroarray is an effectively diagnostic method for prostate cancer.

  19. Uric acid: a modulator of prostate cells and activin sensitivity.

    Science.gov (United States)

    Sangkop, Febbie; Singh, Geeta; Rodrigues, Ely; Gold, Elspeth; Bahn, Andrew

    2016-03-01

    Elevated serum uric acid (SUA) or urate is associated with inflammation and gout. Recent evidence has linked urate to cancers, but little is known about urate effects in prostate cancer. Activins are inflammatory cytokines and negative growth regulators in the prostate. A hallmark of prostate cancer progression is activin insensitivity; however, mechanisms underlying this are unclear. We propose that elevated SUA is associated with prostate cancer counteracting the growth inhibitory effects of activins. The expression of activins A and B, urate transporter GLUT9 and tissue urate levels were examined in human prostate disease. Intracellular and secreted urate and GLUT9 expression were assessed in human prostate cancer cell lines. Furthermore, the effects of urate and probenecid, a known urate transport inhibitor, were determined in combination with activin A. Activin A expression was increased in low-grade prostate cancer, whereas activin B expression was reduced in high-grade prostate cancer. Intracellular urate levels decreased in all prostate pathologies, while GLUT9 expression decreased in benign prostatic hyperplasia, prostatitis and high-grade prostate cancer. Activin responsive LNCaP cells had higher intracellular and lower secreted urate levels than activin-insensitive PC3 cells. GLUT9 expression in prostate cancer cells was progressively lower than in prostate epithelial cells. Elevated extracellular urate was growth promoting in vitro, which was abolished by the gout medication probenecid, and it antagonized the growth inhibitory effects of activins. This study shows for the first time that a change in plasma or intracellular urate levels, possibly involving GLUT9 and a urate efflux transporter, has an impact on prostate cancer cell growth, and that lowering SUA levels in prostate cancer is likely to be therapeutically beneficial. PMID:26910779

  20. Significance of prostatic weight in prostatism

    DEFF Research Database (Denmark)

    Jensen, K M; Bruskewitz, R C; Iversen, P; Madsen, P O

    1983-01-01

    In addition to routine evaluation, 68 patients with prostatism underwent blinded urodynamic testing prior to transurethral prostatectomy and were reexamined symptomatologically and urodynamically at 3 and 12 months after surgery to determine if prostatic weight could predict postoperative outcome...

  1. Anti-proliferative effects of polyphenols from pomegranate rind (Punica granatum L.) on EJ bladder cancer cells via regulation of p53/miR-34a axis.

    Science.gov (United States)

    Zhou, Benhong; Yi, Huilan; Tan, Jun; Wu, Yue; Liu, Gang; Qiu, Zhenpeng

    2015-03-01

    miRNAs and their validated miRNA targets appear as novel effectors in biological activities of plant polyphenols; however, limited information is available on miR-34a mediated cytotoxicity of pomegranate rind polyphenols in cancer cell lines. For this purpose, cell viability assay, Realtime quantitative PCR for mRNA quantification, western blot for essential protein expression, p53 silencing by shRNA and miR-34a knockdown were performed in the present study. EJ cell treatment with 100 µg (GAE)/mL PRE for 48 h evoked poor cell viability and caspase-dependent pro-apoptosis appearance. PRE also elevated p53 protein and triggered miR-34a expression. The c-Myc and CD44 were confirmed as direct targets of miR-34a in EJ cell apoptosis induced by PRE. Our results provide sufficient evidence that polyphenols in PRE can be potential molecular clusters to suppress bladder cancer cell EJ proliferation via p53/miR-34a axis. PMID:25572695

  2. Pharmacological treatment of the benign prostatic hyperplasia

    International Nuclear Information System (INIS)

    Benign prostatic hyperplasia is a common disease in over 50 years-old men consisting in uncontrolled and benign growth of prostatic gland that leads to lower urinary tract symptoms. The etiology of benign prostatic hyperplasia is multifactoral involving the increased conversion of testosterone in dihydrotestosterone by the prostatic 5α-reductase action, which brought about events that encourage the prostate growth (static component) and the increase of the bladder and prostate smooth muscle tone (dynamic component) regulated by the aα1 -adrenoceptors (ADR). The pharmacological treatment of the benign prostatic hyperplasia includes the prostatic 5aα-reductase inhibitors, the aα1-adrenoreceptor blockers, their combined therapy and the phytotherapy. This paper was aimed at presenting the most relevant aspects of the pharmacology of drugs used for treating the benign prostatic hyperplasia, and providing elements to analyze their efficacy, safety and tolerability. To this end, a review was made of the different drugs for the treatment of this pathology and they were grouped according to their mechanism of action. Natural products were included as lipid extracts from Serenoa repens and Pygeum africanum as well as D-004, a lipid extract from Roystonea regia fruits, with proved beneficial effects on the main etiological factors of benign prostatic hyperplasia. D-004 is a prostatic 5a-reductase inhibitor, an aα1-adrenoceptor antagonist, aα 5-lipooxygenase inhibitor and has antioxidant action, all of which reveals a multifactoral mechanism. The results achieved till now indicate that D-004 is a safe and well-tolerated product

  3. Regulation of Cell Proliferation and Migration by miR-203 via GAS41/miR-10b Axis in Human Glioblastoma Cells

    Science.gov (United States)

    Pal, Dhananjaya; Mukhopadhyay, Debasmita; Ramaiah, M. Janaki; Sarma, Pranjal; Bhadra, Utpal; Bhadra, Manika Pal

    2016-01-01

    Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR-203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR-203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma. PMID:27467502

  4. Genomic rearrangements of PTEN in prostate cancer

    Directory of Open Access Journals (Sweden)

    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  5. Oxidative stress in prostate hypertrophy and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Waldemar M. Przybyszewski

    2009-07-01

    Full Text Available Aging, significant impairment of the oxidation/reduction balance, infection, and inflammation are recognized risk factors of benign hyperplasia and prostate cancer. Chronic symptomatic and asymptomatic prostate inflammatory processes generate significantly elevated levels of reactive oxygen and nitrogen species, and halogenated compounds. Prostate cancer patients showed significantly higher lipid peroxidation and lower antioxidant levels in peripheral blood than healthy controls, whereas patients with prostate hyperplasia did not show such symptoms. Oxidative/nitrosative/halogenative stress causes DNA modifications leading to genome instability that may initiate carcinogenesis; however, it was shown that oxidative damage alone is not sufficient to initiate this process. Peroxidation products induced by reactive oxygen and nitrogen species seem to take part in epigenetic mechanisms regulating genome activity. One of the most common changes occurring in more than 90�0of all analyzed prostate cancers is the silencing of GSTP1 gene activity. The gene encodes glutathione transferase, an enzyme participating in detoxification processes. Prostate hyperplasia is often accompanied by chronic inflammation and such a relationship was not observed in prostate cancer. The participation of infection and inflammation in the development of hyperplasia is unquestionable and these factors probably also take part in initiating the early stages of prostate carcinogenesis. Thus it seems that therapeutic strategies that prevent genome oxidative damage in situations involving oxidative/nitrosative/halogenative stress, i.e. use of antioxidants, plant steroids, antibiotics, and non-steroidal anti-inflammatory drugs, could help prevent carcinogenesis.

  6. Mechanism and Function of Angiogenin in Prostate Cancer

    Science.gov (United States)

    Vanli, Nil; Guo-Fu, HU

    2016-01-01

    Angiogenin (ANG), the fifth member of the vertebrate-specific ribonuclease (RNase) A superfamily, is a secreted angiogenic ribonuclease strongly up-regulated in human prostate cancers. ANG is translocated to the nucleus in both prostate cancer epithelial cells and endothelial cells to exert its role in prostate cancer progression by mediating tumor angiogenesis, cancer cell survival and proliferation through rRNA biogenesis. ANG-stimulated rRNA is required not only for prostate intraepithelial neoplasia (PIN) formation, but also for androgen-independent growth of prostate cancer cells. Targeting ANG by various antagonists that inhibit its nuclear translocation, function and/or activity has proven to inhibit prostate cancer growth in animal models. Furthermore, the role of ANG in androgen independence has been firmly established, suggesting a strong rationale for therapeutically targeting ANG in the treatment of castration resistant prostate cancer. PMID:27175049

  7. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

    Science.gov (United States)

    Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Azuma, Haruhito; Lee, Gwo-Shu Mary; Kantoff, Philip W; Sweeney, Christopher J

    2016-05-31

    The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. PMID:27185910

  8. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines

    OpenAIRE

    Ben-Baruch, Adit

    2011-01-01

    Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines ...

  9. Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach

    OpenAIRE

    Costello, Leslie C; Franklin, Renty B; Zou, Jing; Naslund, Michael J

    2015-01-01

    Despite decades of research, no efficacious chemotherapy exists for the treatment of prostate cancer. Malignant prostate zinc levels are markedly decreased in all cases of prostate cancer compared to normal/benign prostate. ZIP1 zinc transporter down regulation decreases zinc to prevent its cytotoxic effects. Thus, prostate cancer is a “ZIP1-deficient” malignancy. A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. Howeve...

  10. Hypothalamus-Pituitary-Thyroid Axis.

    Science.gov (United States)

    Ortiga-Carvalho, Tania M; Chiamolera, Maria I; Pazos-Moura, Carmen C; Wondisford, Fredic E

    2016-01-01

    The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016. PMID:27347897

  11. Prostate cancer stem cells

    OpenAIRE

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  12. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Kumar, V; Palermo, R; Talora, C; Campese, A F; Checquolo, S; Bellavia, D; Tottone, L; Testa, G; Miele, E; Indraccolo, S; Amadori, A; Ferretti, E; Gulino, A; Vacca, A; Screpanti, I

    2014-12-01

    Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols. PMID:24727676

  13. The microRNA-200/Zeb1 axis regulates ECM-dependent β1-integrin/FAK signaling, cancer cell invasion and metastasis through CRKL.

    Science.gov (United States)

    Ungewiss, Christin; Rizvi, Zain H; Roybal, Jonathon D; Peng, David H; Gold, Kathryn A; Shin, Dong-Hoon; Creighton, Chad J; Gibbons, Don L

    2016-01-01

    Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin β1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itgβ1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis. PMID:26728244

  14. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

    Science.gov (United States)

    Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH1A/RA synt...

  15. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hu; Zhu, Chen; Qin, Chao [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Tao, Tao [Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Li, Jie; Cheng, Gong; Li, Pu; Cao, Qiang; Meng, Xiaoxin; Ju, Xiaobing; Shao, Pengfei; Hua, Lixin [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Gu, Min, E-mail: medzhao1980@163.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Yin, Changjun, E-mail: drcjyin@gmail.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2013-03-08

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression.

  16. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    International Nuclear Information System (INIS)

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression

  17. Can Prostate Cancer Be Found Early?

    Science.gov (United States)

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » Can prostate cancer be found ... and symptoms of prostate cancer Tests for prostate cancer Prostate cancer stages Survival rates for prostate cancer Previous ...

  18. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines.

    Science.gov (United States)

    Ben-Baruch, Adit

    2012-08-01

    Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines and of the inflammatory cytokine tumor necrosis factor α (TNFα) in determining cell motility processes that eventually have profound effects on tumor growth and metastasis. First, the effects of inflammatory chemokines such as CCL2 (MCP-1), CCL5 (RANTES) and CXCL8 (IL-8) are described, regulating the inward flow of leukocyte sub-populations with pro-tumoral activities, such as tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), Th17 cells and Tregs. Then, the ability of inflammatory chemokines to induce endothelial cell migration, sprouting and tube formation is discussed, with its implications on tumor angiogenesis. This part is followed by an in depth description of the manners by which TNFα potentiates the above activities of the inflammatory chemokines, alongside with its ability to directly induce migratory processes in the tumor cells thus promoting metastasis. Note worthy is the ability of TNFα to induce in the tumor cells the important process of epithelial-to-mesenchymal transition (EMT). Emphasis is given to the ability of TNFα to establish an inflammatory network with the chemokines, and in parallel to form a cell re-modeling network together with transforming growth factor β (TGFβ). The review concludes by discussing the implications of such networks on disease course, and on the future design of therapeutic measures in cancer. PMID:22190050

  19. [Leptin and hypothalamus-hypophysis-thyroid axis].

    Science.gov (United States)

    Riccioni, G; Menna, V; Lambo, M S; Della Vecchia, R; Di Ilio, C; De Lorenzo, A; D'Orazio, N

    2004-01-01

    The leptin system is a major regulator of food intake and metabolic rate. The leptin, an adipose tissue hormone whose plasma levels reflect energy stores, plays an important rule in the pathogenesis of such eating disorders like bulimia and anorexia. Thyroid hormones are major regulators of energy homeostasis. It is possible that leptin and thyroid hormone exert their actions on thermogenesis and energy metabolism via the same common effector patways. Leptin influences feedback regulation of the hypotalamic TRH-secreting neurons by thyroid hormone. Low serum levels of thyroid hormones reflect a dysfunction of the hypotalamic-pituitary-thyroid (HPT) and hypotalamic-pituitary-adrenal (HPA) axis in patients with nervosa anorexia. Neuroendocrine effects of leptin include effects on the HPT and HPA axis. The aim of this work is to evaluated the interactions between leptina and HPT axis on the basis of recent published works and reviews in literature. PMID:15147079

  20. [Prostate cancer].

    Science.gov (United States)

    Morote, Joan; Maldonado, Xavier; Morales-Bárrera, Rafael

    2016-02-01

    The Vall d'Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow-up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity. Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance. PMID:25727526

  1. Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis.

    Science.gov (United States)

    Rizvi, Fatima; Mathur, Alpana; Kakkar, Poonam

    2015-10-01

    Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI. PMID:26286854

  2. Systematic Structure Modifications of Multi-target Prostate Cancer Drug Candidate Galeterone to Produce Novel Androgen Receptor Down-regulating Agents as an Approach to Treatment of Advanced Prostate Cancer

    Science.gov (United States)

    Purushottamachar, Puranik; Godbole, Abhijit M.; Gediya, Lalji K.; Martin, Marlena S.; Vasaitis, Tadas S.; Kwegyir-Afful, Andrew K.; Ramalingam, Senthilmurugan; Ates-Alagoz, Zeynep; Njar, Vincent C. O.

    2013-01-01

    As part of our program to explore the influence of small structural modifications of our drug candidate, 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16 and C-17 analogs. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both anti-proliferative (AP) and AR degrading (ARD) activities. The most potent anti-proliferative compounds were 3β-(1H-imidazole-1-carboxylate)- 17-(1H-benzimidazol-1-yl)-androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1Hbenzimidazol- 1-yl)-androsta-4,16-diene (36), 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol- 1-yl)-androsta-5,16-diene (43), with GI50 values of 0.87, 1.91 and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43 and 47 could degrade both full-length and truncated AR in CWR22rv1 human prostate cancer cells. With these activities, their potential for development as new drugs for the treatment of all forms of prostate cancer. PMID:23713567

  3. TGF-beta1 suppresses IL-6-induced STAT3 activation through regulation of Jak2 expression in prostate epithelial cells

    Czech Academy of Sciences Publication Activity Database

    Staršíchová, Andrea; Lincová, Eva; Pernicová, Zuzana; Kozubík, Alois; Souček, Karel

    2010-01-01

    Roč. 22, č. 11 (2010), s. 1734-1744. ISSN 0898-6568 R&D Projects: GA MZd NS9600 Grant ostatní: GA ČR(CZ) GA310/07/0961 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : interleukin-6 * transforming growth factor-beta * prostate Subject RIV: BO - Biophysics Impact factor: 4.243, year: 2010

  4. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

    OpenAIRE

    Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J.; Malkowicz, S. Bruce

    2013-01-01

    Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phe...

  5. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α

    OpenAIRE

    Alessio Paone; Roberta Galli; Chiara Gabellini; Dmitriy Lukashev; Donatella Starace; Agnes Gorlach; Paola De Cesaris; Elio Ziparo; Donatella Del Bufalo; Sitkovsky, Michail V.; Antonio Filippini; Anna Riccioli

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible...

  6. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α1

    OpenAIRE

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V.; Filippini, Antonio; Riccioli, Anna

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible...

  7. Prostate carcinoma

    International Nuclear Information System (INIS)

    Prostate cancer is the most common malignancy in men in Europe, North America, and in some African states. Early diagnosis in an asymptomatic stage is possible through the combination of digitorectal examination, PSA serum testing, and systematic biopsy. However, general screening is so far not recommended by the Urologic Societies, because the efficiency is not yet proved. Imaging is also not recommended for first-line screening. Novel functional methods of transrectal ultrasound (TRUS) and endorectal MRI can improve accuracy of tumor detection to more than 90% and can be used for TRUS- and now also MRI-guided biopsy leading to two- to threefold higher tumor detection rates. There is general agreement that all men over 50 years of age should be informed about the possibilities, benefits, and risks of the available methods for early tumor detection. (orig.)

  8. Prostate cancer staging

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000397.htm Prostate cancer staging To use the sharing features on this ... trials you may be able to join How Prostate Cancer Staging is Done Initial staging is based on ...

  9. Prostate cancer screenings

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000846.htm Prostate cancer screenings To use the sharing features on this ... Intern Med . 2011;155(11):762-71. National Cancer Institute. Prostate Cancer Screening -- for health professionals. Revised April 2, ...

  10. Cryotherapy for prostate cancer

    Science.gov (United States)

    Cryotherapy uses very cold temperatures to freeze and kill prostate cancer cells. The goal of cryosurgery is ... Possible short-term side effects of cryotherapy for prostate ... of the penis or scrotum Problems controlling your bladder (more ...

  11. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... In the United States, one in ten men will develop prostate cancer in their lifetime. Age is ... disease that's very benevolent in its behavior. Men will develop prostate cancer and live the rest of ...

  12. Prostate resection - minimally invasive

    Science.gov (United States)

    ... microwave thermotherapy; TUMT; BPH - resection; Benign prostatic hyperplasia (hypertrophy) - resection; Prostate - enlarged - resection ... passing an instrument through the opening in your penis (meatus). You will be given general anesthesia (asleep ...

  13. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... like to do is just do a rectal examination and feel that prostate. Narrator: The other necessary ... they do have an abnormality in their rectal examination does not mean that they have prostate cancer. ...

  14. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... United States, one in ten men will develop prostate cancer in their lifetime. Age is the most important risk factor in prostate cancer -- the longer a man lives the more likely ...

  15. Screening for Prostate Cancer

    Science.gov (United States)

    ... of Internal Medicine Summaries for Patients Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee ... Physicians The full report is titled “Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee ...

  16. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the best thing to ... prostate gland. Usually these are accompanied by a biopsy -- a sampling of the prostate tissue with a ...

  17. Prostate Cancer Screening

    Science.gov (United States)

    ... treat. There is no standard screening test for prostate cancer. Researchers are studying different tests to find those ... PSA level may be high if you have prostate cancer. It can also be high if you have ...

  18. Prostate Cancer Prevention

    Science.gov (United States)

    ... prostate cancer increases as men get older. Family history of prostate cancer A man whose father, brother, ... some foods, such as green vegetables, beans and orange juice. Folic acid is a man-made form ...

  19. Enlarged prostate - after care

    Science.gov (United States)

    BPH - self-care; Benign prostatic hypertrophy - self-care; Benign prostatic hyperplasia - self-care ... exercises ( Kegel exercises ) that strengthen the pelvic floor muscles. Doing these exercise may help with leaking or ...

  20. About the Prostate

    Science.gov (United States)

    ... DRE) is a useful screening test. Benign prostatic hypertrophy ( BPH ), a non-cancerous prostate condition, typically develops ... Under normal circumstances, the urinary sphincters (bands of muscle at the base of the bladder and at ...

  1. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... important risk factor in prostate cancer -- the longer a man lives the more likely he is to ... men confront the reality of prostate cancer on a visit to their urologist. John Bertini, M.D.: ...

  2. Prostate cancer in Denmark

    DEFF Research Database (Denmark)

    Brasso, K; Friis, S; Kjaer, S K;

    1998-01-01

    To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period.......To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period....

  3. Prostate Cancer Foundation

    Science.gov (United States)

    ... News Faces of Prostate Cancer [4] Survivors Everyday Heroes PCF Researchers Share your story About PCF [1] ... in advanced prostate cancer patients regardless of family history, and are associated with poorer responses to hormonal ...

  4. The PI3K/AKT pathway in the pathogenesis of prostate cancer.

    Science.gov (United States)

    Chen, Huixing; Zhou, Lan; Wu, Xiaorong; Li, Rongbing; Wen, Jiling; Sha, Jianjun; Wen, Xiaofei

    2016-01-01

    Despite recent advances in our understanding of the biological behavior of prostate cancer (PCa), PCa is becoming the most common malignancy in men worldwide. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in prostate carcinogenesis. Inflammatory cytokines (CCR9, IL-6, and TLR3) regulate PI3K/AKT signaling during apoptosis of PCa cells, and PI3K/AKT signaling participates with androgen-, 1alpha,25(OH)2-vitamin D3-, and prostaglandin-associated mechanisms and is regulated by ErbB, EGFR, and the HER family during cell growth. During metastasis of PCa cells, the PI3K/AKT/NF-kappaB/BMP-2-Smad axis, PTEN/PI3K/AKT pathway, and PI3K/AKT/mTOR signaling regulates tumor cell metastasis and invasion. The present review focuses on the PI3K/AKT signal pathway and discusses the role of the PI3K/AKT signal pathway in PCa tumorigenesis. PMID:27100493

  5. Sox7 is an independent checkpoint for β-catenin function in prostate and colon epithelial cells

    OpenAIRE

    Guo, Lizheng; Diansheng ZHONG; Lau, Stephen; Liu, Xiuju; Dong, Xue-Yuan; Sun, Xiaodong; Yang, Vincent W.; Vertino, Paula M.; Moreno, Carlos; Varma, Vijay; Jin-Tang, Dong; Wei, Zhou

    2008-01-01

    The presence of somatic β-catenin mutations in some prostate cancers implies that aberrant WNT signaling is involved in the cancer’s development. Although β-catenin stability is regulated by a multi-component destruction complex, mutational alterations of β-catenin or other components of the destruction complexes are rare in prostate tumors. Therefore, β-catenin may be regulated by another protein in the prostate. In fact, recent linkage and somatic deletion analyses in prostate cancers revea...

  6. miR-18a promotes cell proliferation of esophageal squamous cell carcinoma cells by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis.

    Science.gov (United States)

    Zhang, Weiguo; Lei, Caipeng; Fan, Junli; Wang, Jing

    2016-08-12

    Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Cyclin D1 is overexpressed and plays an important role in the carcinogenesis of ESCC; however the mechanism of the deregulation of Cyclin D1 in ESCC remains to be determined. In the study, we found that miR-18a promotes the expression Cyclin D1 by targeting PTEN in eophageal squamous cell carcinoma TE13 and Eca109 cells. Transfection of miR-18a mimetics increased cyclin D1, while transfection of miR-18a antagomir decreased D1. Moreover, miR-18a-mediated upregulation of cyclin D1 was accompanied with downregulation of PTEN, which is a direct target of miR-18a, and increase of the phosphorylation of AKT and S6K1. In addition, pharmacologic inhibition of AKT or mTOR kinases abolished the increase of cyclinD1 by miR-18a, which was accompanied with decreased phosphorylation of RbS780 and inhibition of cell proliferation. Our results demonstrated the upregulation of miR-18a promoted cell proliferation by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis, suggesting that small molecule inhibitors of AKT-mTOR signaling are potential agents for the treatment of ESCC patients with upregulation of miR-17-92 cluster. PMID:27291152

  7. Tumor-Suppressive Activity of Lunatic Fringe in Prostate through Differential Modulation of Notch Receptor Activation

    Directory of Open Access Journals (Sweden)

    Shubing Zhang

    2014-02-01

    Full Text Available Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng, which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44+CD24− and CD49f+CD24− stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

  8. An APC:WNT counter-current-like mechanism regulates cell division along the colonic crypt axis: a mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development.

    Directory of Open Access Journals (Sweden)

    Bruce M Boman

    2013-11-01

    Full Text Available APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside. WNT signaling, in contrast, is high at the bottom (where SCs reside and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g. survivin are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric. APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly-proliferating cells during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes.

  9. Retraction: "Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on January 5, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 5A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH. 2010. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways. J Cell Biochem 109:726-736; doi: 10.1002/jcb.22451. PMID:27301887

  10. Retraction: "Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on July 23, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 1B and 3A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Wojewoda C, Miele L, Sarkar FH. 2011. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem 112:78-88; doi: 10.1002/jcb.22770. PMID:27301889

  11. The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup

    Directory of Open Access Journals (Sweden)

    Sowden Jane C

    2006-12-01

    Full Text Available Abstract Background Polarised gene expression is thought to lead to the graded distribution of signaling molecules providing a patterning mechanism across the embryonic eye. Bone morphogenetic protein 4 (Bmp4 is expressed in the dorsal optic vesicle as it transforms into the optic cup. Bmp4 deletions in human and mouse result in failure of eye development, but little attempt has been made to investigate mammalian targets of BMP4 signaling. In chick, retroviral gene overexpression studies indicate that Bmp4 activates the dorsally expressed Tbx5 gene, which represses ventrally expressed cVax. It is not known whether the Tbx5 related genes, Tbx2 and Tbx3, are BMP4 targets in the mammalian retina and whether BMP4 acts at a distance from its site of expression. Although it is established that Drosophila Dpp (homologue of vertebrate Bmp4 acts as a morphogen, there is little evidence that BMP4 gradients are interpreted to create domains of BMP4 target gene expression in the mouse. Results Our data show that the level of BMP4 signaling is critical for the regulation of distinct Tbx2, Tbx3, Tbx5 and Vax2 gene expression domains along the dorso-ventral axis of the mouse optic cup. BMP4 signaling gradients were manipulated in whole mouse embryo cultures during optic cup development, by implantation of beads soaked in BMP4, or the BMP antagonist Noggin, to provide a local signaling source. Tbx2, Tbx3 and Tbx5, showed a differential response to alterations in the level of BMP4 along the entire dorso-ventral axis of the optic cup, suggesting that BMP4 acts across a distance. Increased levels of BMP4 caused expansion of Tbx2 and Tbx3, but not Tbx5, into the ventral retina and repression of the ventral marker Vax2. Conversely, Noggin abolished Tbx5 expression but only shifted Tbx2 expression dorsally. Increased levels of BMP4 signaling caused decreased proliferation, reduced retinal volume and altered the shape of the optic cup. Conclusion Our findings suggest

  12. Prostate Cancer: Symptoms, Diagnosis and Treatment

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Prostate Cancer: Symptoms, Diagnosis and Treatment Past Issues / Winter ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  13. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  14. Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway.

    Science.gov (United States)

    Li, Qi; Lai, Yiming; Wang, Chengbin; Xu, Guibin; He, Zheng; Shang, Xiaohong; Sun, Yi; Zhang, Fan; Liu, Leyuan; Huang, Hai

    2016-01-01

    Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC-3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKα/β, p-IKKα/β, IKBα and p-IKBα as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-κB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer. PMID:26497618

  15. Hormone therapy for prostate cancer

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000908.htm Hormone therapy for prostate cancer To use the sharing ... helps slow the growth of prostate cancer. Male Hormones and Prostate Cancer Androgens are male sex hormones. ...

  16. 6 Common Cancers - Prostate Cancer

    Science.gov (United States)

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Prostate Cancer Past Issues / Spring 2007 Table of Contents ... early screening. Photo: AP Photo/Danny Moloshok Prostate Cancer The prostate gland is a walnut-sized structure that makes ...

  17. Vaccine Treatment for Prostate Cancer

    Science.gov (United States)

    ... Preventing and treating prostate cancer spread to bones Vaccine treatment for prostate cancer Sipuleucel-T (Provenge) is ... less advanced prostate cancer. Possible side effects of vaccine treatment Side effects from the vaccine tend to ...

  18. CSR1 Suppresses Tumor Growth and Metastasis of Prostate Cancer

    OpenAIRE

    Yu, Guoying; Tseng, George C.; Yu, Yan Ping; Gavel, Tim; Nelson, Joel; Wells, Alan; Michalopoulos, George; Kokkinakis, Demetrius; Luo, Jian-Hua

    2006-01-01

    Prostate cancer is frequent among men over 45 years of age, but it generally only becomes lethal with metastasis. In this study, we identified a gene called cellular stress response 1 (CSR1) that was frequently down-regulated and methylated in prostate cancer samples. Survival analysis indicated that methylation of the CSR1 promoter, and to a lesser extent down-regulation of CSR1 protein expression, was associated with a high rate of prostate cancer metastasis. Forced expression of CSR1 in pr...

  19. Study on NDRG3 in Mesenchyma of Prostate

    Institute of Scientific and Technical Information of China (English)

    Wei-qun WANG; Yu-hua LI; Ai-zhen HONG; Biao-yang LIN; Xiao-feng JIA; Yang LI; Run-sheng LI

    2008-01-01

    Objective To study expression of NDRG3 in prostatic mesenchyma and effect of exogenous NDRG3 on prostatic stromal cells. Methods Immunohistochemical analysis was used to check expression of NDRG3 in prostate mesnenchyma.The WPMY-1 prostate immortalized mesenchyma cell line was stably-transfected with a NDRG3 gene expression vector.The NDRG3-stable transfected WPMY-1 sublines were studied along with parental and empty vector transfected WPMY-1 cells as controls.RT-PCR technology was applied to identity downstream gene expression under regulation of NDRG3 expression. Results Expression of DNRG3 was observed in prostate cancer mesenchyma,over-expression of NDRG3 in WPMY-1 cell up-regulated expression of chemotatic factors—CXCL3 and CXCL5. Conclusion Expression of stromal NDRG3 in prostate cancer specimens is significantly higher than that in benign prostatic hypertrophy(BPH)sample.There is a remarkable difference between the two groups of samples,NDRG3 may be related to angiogenesis in prostatic mesenchyma.

  20. Triple axis spectrometers

    International Nuclear Information System (INIS)

    Conventional triple-axis neutron spectroscopy was developed by Brockhouse over thirty years ago' and remains today a versatile and powerful tool for probing the dynamics of condensed matter. The original design of the triple axis spectrometer is technically simple and probes momentum and energy space on a point-by-point basis. This ability to systematically probe the scattering function in a way which only requires a few angles to be moved under computer control and where the observed data in general can be analysed using a pencil and graph paper or a simple fitting routine, has been essential for the success of the method. These constraints were quite reasonable at the time the technique was developed. Advances in computer based data acquisition, neutron beam optics, and position sensitive area detectors have been gradually implemented on many triple axis spectrometer spectrometers, but the full potential of this has not been fully exploited yet. Further improvement in terms of efficiency (beyond point by point inspection) and increased sensitivity (use of focusing optics whenever the problem allows it) could easily be up to a factor of 10-20 over present instruments for many problems at a cost which is negligible compared to that of increasing the flux of the source. The real cost will be in complexity - finding the optimal set-up for a given scan and interpreting the data as the they are taken. On-line transformation of the data for an appropriate display in Q, ω space and analysis tools will be equally important for this task, and the success of these new ideas will crucially depend on how well we solve these problems. (author)

  1. Hibiscus sabdariffa Leaf Extract Inhibits Human Prostate Cancer Cell Invasion via Down-Regulation of Akt/NF-κB/MMP-9 Pathway

    Science.gov (United States)

    Chiu, Chun-Tang; Chen, Jing-Hsien; Chou, Fen-Pi; Lin, Hui-Hsuan

    2015-01-01

    Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non-cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-κB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-κB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-κB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells. PMID:26115086

  2. Hibiscus sabdariffa Leaf Extract Inhibits Human Prostate Cancer Cell Invasion via Down-Regulation of Akt/NF-kB/MMP-9 Pathway.

    Science.gov (United States)

    Chiu, Chun-Tang; Chen, Jing-Hsien; Chou, Fen-Pi; Lin, Hui-Hsuan

    2015-07-01

    Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non-cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-κB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-kB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-kB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells. PMID:26115086

  3. Anti-inflammatory effect and prostate gene expression profiling of steryl ferulate on experimental rats with non-bacterial prostatitis.

    Science.gov (United States)

    Hu, Yinzhou; Xiong, Lina; Huang, Weisu; Cai, Huafang; Luo, Yanxi; Zhang, Ying; Lu, Baiyi

    2014-06-01

    Steryl ferulate (SF) is a bioactive mixture extracted from rice bran and shows higher inhibitory activity against inflammation than the corresponding free sterols. In this study, the aim was to investigate the anti-inflammatory effect and prostate gene expression profiling of SF using a Xiaozhiling-induced non-bacterial prostatitis (NBP) rat model. The anti-inflammatory effect was evaluated by prostate weight, prostate index, acid phosphatase, density of lecithin corpuscles (DLC), white blood cell count (WBC), and prostatic histologic section. Prostate gene expression profiling was assessed by a cDNA microarray and validated by quantitative real-time PCR of five selected genes. Pathway analysis and Gene ontology (GO) analysis were applied to determine the roles of these differentially expressed genes involved in these biological pathways or GO terms. SF treatment could significantly inhibit prostate weight, prostate index, total acid phosphatase, prostatic acid phosphatase and WBC, suppress the severity of histological lesion and increase the DLC. Compared with the control group, the SF treatment group contained 238 up-regulated genes and 111 down-regulated genes. GO analysis demonstrated that the most significant expression genes were closely related to the terms of fibrinolysis, inflammatory response, high-density lipoprotein particle, protein-lipid complex, enzyme inhibitor activity, peptidase inhibitor activity and others. Canonical pathway analysis indicated five pathways were significantly regulated, which were associated with inflammation and tumorgenesis. In conclusion, SF may be used as a health supplement to prevent NBP, in that it could inhibit prostate inflammation in NBP patients by affecting the expression of genes in the related GO terms and pathways. PMID:24686498

  4. Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors

    International Nuclear Information System (INIS)

    Typical high throughput microarrays experiments compare gene expression across two specimen classes – an experimental class and baseline (or comparison) class. The choice of specimen classes is a major factor in the differential gene expression patterns revealed by these experiments. In most studies of prostate cancer, histologically malignant tissue is chosen as the experimental class while normal appearing prostate tissue adjacent to the tumor (adjacent normal) is chosen as the baseline against which comparison is made. However, normal appearing prostate tissue from tumor free organ donors represents an alterative source of baseline tissue for differential expression studies. To examine the effect of using donor normal tissue as opposed to adjacent normal tissue as a baseline for prostate cancer expression studies, we compared, using oligonucleotide microarrays, the expression profiles of primary prostate cancer (tumor), adjacent normal tissue and normal tissue from tumor free donors. Statistical analysis using Significance Analysis of Microarrays (SAM) demonstrates the presence of unique gene expression profiles for each of these specimen classes. The tumor v donor expression profile was more extensive that the tumor v adjacent normal profile. The differentially expressed gene lists from tumor v donor, tumor v adjacent normal and adjacent normal v donor comparisons were examined to identify regulated genes. When donors were used as the baseline, similar genes are highly regulated in both tumor and adjacent normal tissue. Significantly, both tumor and adjacent normal tissue exhibit significant up regulation of proliferation related genes including transcription factors, signal transducers and growth regulators compared to donor tissue. These genes were not picked up in a direct comparison of tumor and adjacent normal tissues. The up-regulation of these gene types in both tissue types is an unexpected finding and suggests that normal appearing prostate tissue

  5. Estrogen receptors in the human male prostatic urethra and prostate in prostatic cancer and benign prostatic hyperplasia

    DEFF Research Database (Denmark)

    Bødker, A; Bruun, J; Balslev, E;

    1999-01-01

    Estrogen receptors (ERs) in the prostate and prostatic urethra were examined in 33 men with benign prostatic hyperplasia (BPH) and in 11 with prostate cancer (PC). The Abbot monoclonal ER-ICA assay was used for immunohistochemical investigation. In the BPH group, ERs were revealed in the prostatic...... stroma in eight cases and in the glandular epithelium in one. In four cases ERs were seen in the prostatic stroma and in the glandular epithelium. In the prostatic urethra, ERs were found in 19 cases located in the urothelium, lamina propria and/or periurethral glands. In the PC group, ERs were...... demonstrated in the prostatic stroma and/or prostatic urethra in 6 out of 11 cases. In both BPH and PC patients, immunoreactivity was weak and confined to few cells, indicating low ER content in the prostate as well as in the prostatic urethra. Dextran-coated charcoal (DCC) analysis was used for detection and...

  6. Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells

    Science.gov (United States)

    Jensen, Ana R.; Saito, Y. David; Liao, Chuanhong; Dai, Jinlu; Keller, Evan T.; Al-Ahmadie, Hikmat; Haché, Kelly Dakin; Usatyuk, Peter; Sievert, Margarit; Paner, Gladell P.; Yala, Soheil; Cervantes, Gustavo M.; Natarajan, Viswanathan; Salgia, Ravi; Posadas, Edwin M.

    2011-01-01

    Purpose Fyn is a member of the Src family of kinases that we have previously shown to be overexpressed in prostate cancer. This study defines the biological impact of Fyn inhibition in cancer using a PC3 prostate cancer model. Experimental Design Fyn expression was suppressed in PC3 cells using an shRNA against Fyn (PC3/FYN-). Knockdown cells were characterized using standard growth curves and time-lapse video microscopy of wound assays and Dunn Chamber assays. Tissue microarray analysis was used to verify the physiologic relevance of the HGF/MET axis in human samples. Flank injections of nude mice were performed to assess in vivo growth characteristics. Results HGF was found to be sufficient to drive Fyn mediated events. Compared to control transductants (PC3/Ctrl), PC3/FYN- showed a 21% decrease in growth at 4 days (P=0.05). PC3/FYN- cells were 34% longer than control cells (P=0.018) with 50% increase in overall surface area (P<0.001). Furthermore, when placed in a gradient of HGF, PC3/FYN- cells showed impaired directed chemotaxis down an HGF gradient in comparison to PC3/Ctrl (P=0.001) despite a 41% increase in cellular movement speed. In vivo studies showed 66% difference of PC3/FYN- cell growth at 8 weeks using bidimensional measurements (P=0.002). Conclusions Fyn plays an important role in prostate cancer biology by facilitating cellular growth and by regulating directed chemotaxis- a key component of metastasis. This finding bears particular translational importance when studying the effect of Fyn inhibition in human subjects. PMID:21364031

  7. Preferred axis in cosmology

    CERN Document Server

    Zhao, Wen

    2016-01-01

    The foundation of modern cosmology relies on the so-called cosmological principle which states an homogeneous and isotropic distribution of matter in the universe on large scales. However, recent observations, such as the temperature anisotropy of the cosmic microwave background (CMB) radiation, the motion of galaxies in the universe, the polarization of quasars and the acceleration of the cosmic expansion, indicate preferred directions in the sky. If these directions have a cosmological origin, the cosmological principle would be violated, and modern cosmology should be reconsidered. In this paper, by considering the preferred axis in the CMB parity violation, we find that it coincides with the preferred axes in CMB quadrupole and CMB octopole, and they all align with the direction of the CMB kinematic dipole. In addition, the preferred directions in the velocity flows, quasar alignment, anisotropy of the cosmic acceleration, the handedness of spiral galaxies, and the angular distribution of the fine-structu...

  8. The experience of using sonoelastography of prostate in prostatic diseases

    Directory of Open Access Journals (Sweden)

    P. S. Zubeev

    2014-11-01

    Full Text Available Objective. To assess sonoelastography opportunities in differential diagnosis of prostatic diseases; to place sonoelastography in general algorithm of prostatic diseases diagnostics.Materials and methods. 91 patients under examination were divided into three groups. The first group included 21 patients (23.1 % with suspected prostate carcinoma, later they underwent puncture multifocal biopsy of prostate with morphological verification of prostate carcinoma. The second group consisted of 51 patients (56.0 % with benign prostatic hyperplasia, and in the third group there were 19 patients (20.9 % with acute and chronic prostatitis.Results. 91 patients with different prostatic diseases were examined. There were defined PSA (prostate specific antigen level, and performed TRUS (transrectal ultrasound, biopsy and sonoelastography of prostate. In 72 patients SEG (sonoelastography-picture of prostate was compared to morphological diagnosis. According to SEG findings, 43 (81.1 % patients were revealed to have the areas of reduced compliance due to what malignancy in prostate gland (PG was excluded. Morphological diagnosis of prostate carcinoma was confirmed in 21 patients. In 51 patients SEG-picture corresponded to benign process confirmed by histology.Conclusion. Sonoelastography is a modern diagnostic technique of prostatic diseases, seminal vesicles, paraprostatic space. The distinguished mapping types enable to make differential diagnosis of different prostatic pathological processes. Sonoelastography improves prostate carcinoma diagnostics and staging, and also has economic significance value when compared to MRP (magnetic resonance tomography with bolus contrast.

  9. Activation of the hedgehog pathway in advanced prostate cancer

    Directory of Open Access Journals (Sweden)

    McCormick Frank

    2004-10-01

    Full Text Available Abstract Background The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications. Results Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP, are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu protein, a negative regulator of the hedgehog pathway. We find that Su(Fu protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu. Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27. High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3. We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells. Conclusion Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have

  10. Prostate-Specific Antigen (PSA) Test

    Science.gov (United States)

    ... Understanding Laboratory Tests Prostate Cancer—Patient Version Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Tumor Markers Understanding Prostate Changes: A Health Guide for Men ...

  11. Stromal mesenchyme cell genes of the human prostate and bladder

    Directory of Open Access Journals (Sweden)

    Pascal Laura E

    2005-12-01

    Full Text Available Abstract Background Stromal mesenchyme cells play an important role in epithelial differentiation and likely in cancer as well. Induction of epithelial differentiation is organ-specific, and the genes responsible could be identified through a comparative genomic analysis of the stromal cells from two different organs. These genes might be aberrantly expressed in cancer since cancer could be viewed as due to a defect in stromal signaling. We propose to identify the prostate stromal genes by analysis of differentially expressed genes between prostate and bladder stromal cells, and to examine their expression in prostate cancer. Methods Immunohistochemistry using antibodies to cluster designation (CD cell surface antigens was first used to characterize the stromas of the prostate and bladder. Stromal cells were prepared from either prostate or bladder tissue for cell culture. RNA was isolated from the cultured cells and analyzed by DNA microarrays. Expression of candidate genes in normal prostate and prostate cancer was examined by RT-PCR. Results The bladder stroma was phenotypically different from that of the prostate. Most notable was the presence of a layer of CD13+ cells adjacent to the urothelium. This structural feature was also seen in the mouse bladder. The prostate stroma was uniformly CD13-. A number of differentially expressed genes between prostate and bladder stromal cells were identified. One prostate gene, proenkephalin (PENK, was of interest because it encodes a hormone. Secreted proteins such as hormones and bioactive peptides are known to mediate cell-cell signaling. Prostate stromal expression of PENK was verified by an antibody raised against a PENK peptide, by RT-PCR analysis of laser-capture microdissected stromal cells, and by database analysis. Gene expression analysis showed that PENK expression was down-regulated in prostate cancer. Conclusion Our findings show that the histologically similar stromas of the prostate and

  12. Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

    Science.gov (United States)

    Sonnemann, Jürgen; Gekeler, Volker; Sagrauske, Antje; Müller, Cornelia; Hofmann, Hans-Peter; Beck, James F

    2004-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL. PMID:15252138

  13. CYP17 inhibitors for prostate cancer therapy.

    Science.gov (United States)

    Vasaitis, Tadas S; Bruno, Robert D; Njar, Vincent C O

    2011-05-01

    Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors. PMID:21092758

  14. Clinical Studies on Treatment of Chronic Prostatitis with Acupuncture and Mild Moxibustion

    Institute of Scientific and Technical Information of China (English)

    Yu Yang; Kang Jingli; Duan Shumin

    2005-01-01

    To observe the therapeutic effect of acupuncture and mild moxibustion on chronic prostatitis and to probe into the mechanism of the therapy. Two hundred patients with chronic prostatitis were randomly divided into two groups so as to observe respectively the changes in clinical symptoms, count of WBC and lecithin corpuscles in succus prostaticus, prostatic capcules and internal echo, tenderness and elasticity of prostate by palpation before and after treatment. After treatment, a remarkable improvement was found in clinical symptoms, succus prostaticus test and ultrasonic examination in the treatment group with a statistically significant difference (P<0.05) as compared to the control group. The treatment of chronic prostatitis with acupuncture and mild moxibustion can remove the stagnation of succus prostaticus, improve the blood circulation in prostate, inhibit or kill the pathogenic micro-organisms, strengthen or regulate the immune function of the patients, improve local blood circulation, eliminate the accumulation of secretion and relieve the obstruction of the prostatic ducts.

  15. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  16. Detecting Prostate Cancer

    Science.gov (United States)

    ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  17. Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

    Science.gov (United States)

    Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells, and ...

  18. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer

    OpenAIRE

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Seve...

  19. Optimizing prostate biopsy for repeat transrectal prostate biopsies patients

    Institute of Scientific and Technical Information of China (English)

    Xiaojun Deng; Jianwei Cao; Feng Liu; Weifeng Wang; Jidong Hao; Jiansheng Wan; Hui Liu

    2014-01-01

    Objective:Diagnosis of patients with negative prostate biopsy and persistent suspicion of prostate cancer re-mains a serious problem. In this study, we investigated the application of optimizing prostate biopsy for patients who need repeat prostate biopsy. Methods:In this prospective, non-randomized phase-I clinical trial, the prostate cancer detection rate of initial detection scheme was compared with optimizing prostate biopsy scheme. The number of punctures of initial detection scheme was the same as that of optimizing prostate biopsy scheme. The puncture direction of optimizing prostate biopsy was a 45° angle to the sagittal plane from front, middle, and back. The two cores from each lateral lobe were horizontal y inwardly inclined 45°. Results:A total of 45 patients with initial negative biopsy for cancer were received the optimizing prostate biopsy scheme. The cancer detection rate was 17.8%(8/45), and prostate intraepithelial neoplasm (PIN) was 6.7%(3/45). The pa-tients receiving repeat transrectal prostate biopsies were pathological y diagnosed as lower Gleason grade prostate cancers. Conclusion:The cancer detection rate of repeat biopsy prostate cancer is lower than that of initial biopsy. Our study showed that the optimizing prostate biopsy is important to improve the detection rate of repeat transrectal prostate biopsies patients.

  20. Prostate cancer; Cancer de la prostate

    Energy Technology Data Exchange (ETDEWEB)

    Vieillot, S.; Fenoglietto, P.; Ailleres, N.; Hay, M.H.; Dubois, J.B.; Azria, D. [Departement de cancerologie radiotherapie, Universite Montpellier I, CRLC Val d' Aurelle, 34 - Montpellier (France)

    2010-07-01

    Radiation therapy is now widely accepted as an efficacious treatment of localized prostate cancer. The technical developments of recent years have enabled the evolution of a three-dimensional conformal radiotherapy, offering a better adaptation of the dose distribution, and leading therefore to preserve organs at risk. In addition, the required dose delivered to the target volume permit physician to increase the total dose if necessary. This requires a thorough knowledge of the radio-anatomy of the prostate, the natural history of the disease but also the ballistics and dosimetry. The objectives of this work were to detail epidemiology and radio-anatomy of the prostate cancer. In addition, conformal radiation modalities are illustrated by a case report. (authors)

  1. Prostate Cancer Screening (Beyond the Basics)

    Science.gov (United States)

    ... best in your individual situation. WHAT IS PROSTATE CANCER? — Prostate cancer is a cancer of the prostate, a ... most of them do not die from their cancer. Prostate cancer often grows so slowly that many men ...

  2. What Tests Can Detect Prostate Cancer?

    Science.gov (United States)

    ... saved articles window. My Saved Articles » My ACS » Prostate Cancer Prevention and Early Detection + - Text Size Download Printable Version [ ... coverage for prostate cancer screening Additional resources for prostate cancer prevention and early detection References: Prostate cancer prevention and ...

  3. Ultrasound- and MRI-Guided Prostate Biopsy

    Science.gov (United States)

    ... Index A-Z Ultrasound- and MRI-Guided Prostate Biopsy Ultrasound- and MRI-guided prostate biopsy uses imaging ... Biopsy? What is Ultrasound- and MRI-guided Prostate Biopsy? Ultrasound- and MRI-guided prostate biopsies are performed ...

  4. The link between benign prostatic hyperplasia and prostate cancer.

    Science.gov (United States)

    Ørsted, David D; Bojesen, Stig E

    2013-01-01

    Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH as a causal factor for prostate cancer development could improve the accuracy of prognostication and expedite intervention, potentially reducing the number of men who die from prostate cancer. PMID:23165396

  5. The hedgehog/Gli signaling paradigm in prostate cancer

    OpenAIRE

    Chen, Mengqian; Carkner, Richard; Buttyan, Ralph

    2011-01-01

    Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior....

  6. A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

  7. Methods for Prostate Biopsy

    OpenAIRE

    M. Ghafoori

    2008-01-01

    Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-spe...

  8. Prostate Epithelial Pten/TP53 Loss Leads to Transformation of Multipotential Progenitors and Epithelial to Mesenchymal Transition

    OpenAIRE

    Martin, Philip; Liu, Yen-Nien; Pierce, Rachel; Abou-Kheir, Wassim; Casey, Orla; Seng, Victoria; Camacho, Daniel; Simpson, R. Mark; Kelly, Kathleen

    2011-01-01

    Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4+Ptenfl/flTP53fl/fl model of prostate cancer, we describe the histological and metastatic prop...

  9. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    Directory of Open Access Journals (Sweden)

    MartinTenniswood

    2014-05-01

    Full Text Available Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.

  10. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... have other tests, such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the ... exam or PSA test indicates an abnormality, an ultrasound image is made of the prostate gland. Usually ...

  11. Prostate radiation - discharge

    Science.gov (United States)

    ... day. Avoid orange juice, grapefruit juice, and other citrus juices if they make the bowel or bladder ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Cancer Browse the Encyclopedia A.D. ...

  12. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... the more likely he is to develop the disease. Physician: Come on back, first room. Narrator: Most ... cancer. Prostate cancer is really a spectrum of diseases where on one end of the spectrum there ...

  13. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... have by having their blood sampled and what we look for is a particular glyco-protein that's ... that they have prostate cancer. It means that we're concerned about it and they should go ...

  14. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... abnormal and raises the index of suspicion that cancer may be present. Narrator: While the use of ... examination does not mean that they have prostate cancer. It means that we're concerned about it ...

  15. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled ... be present. Narrator: While the use of the test remains controversial, a normal PSA level is considered ...

  16. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  17. Prostate brachytherapy - discharge

    Science.gov (United States)

    ... into your prostate. They were inserted through your perineum (the area between the scrotum and the anus). ... feel the urge to urinate more often. Your perineum may be tender and bruised. You can use ...

  18. Prostate Cancer Screening

    Science.gov (United States)

    ... man's bladder that produces fluid for semen. Cancer screening is looking for cancer before you have any ... be easier to treat. There is no standard screening test for prostate cancer. Researchers are studying different ...

  19. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... PSA stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled and what we look for is a particular glyco-protein that's found in the blood. ...

  20. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having ... detection is the digital rectal exam. Barry Trevithick: It doesn't make sense to be afraid of ...

  1. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... visit to their urologist. John Bertini, M.D.: It's a wide variety of reasons why they might ... have a prostate. Most men don't pronounce it correctly and wouldn't know where it's located ...

  2. Screening for Prostate Cancer

    Science.gov (United States)

    ... absolute reduction in mortal- ity. Preliminary results from PIVOT (Prostate Cancer In- tervention Versus Observation Trial), in ... early PSA screening era, prelim- inary findings from PIVOT show that, after 12 years, in- tention to ...

  3. Prostate cancer staging

    Science.gov (United States)

    ... effects of treatment The chance that treatment can cure your cancer or help you in other ways With stage ... III prostate cancer, the main goal is to cure the cancer by treating it and keeping it from coming ...

  4. Marked heterogeneity of ERG expression in large primary prostate cancers.

    Science.gov (United States)

    Minner, Sarah; Gärtner, Michael; Freudenthaler, Fabian; Bauer, Melanie; Kluth, Martina; Salomon, Georg; Heinzer, Hans; Graefen, Markus; Bokemeyer, Carsten; Simon, Ronald; Sauter, Guido; Schlomm, Thorsten; Wilczak, Waldemar

    2013-01-01

    Approximately 50% of prostate cancers are characterized by TMPRSS2 (transmembrane protease serine 2)-ERG (avian v-ets erythroblastosis virus E26 oncogene homolog) gene fusions resulting in an androgen-regulated overexpression of the transcription factor ERG. Some studies have suggested prognostic or predictive relevance of ERG status in prostate cancer. Such concepts could be impaired by extensive ERG heterogeneity in analyzed tumors. The aim of this study was to analyze the extent of heterogeneity for TMPRSS2-ERG fusion in prostate cancer. To enable large-scale studies on the extent of heterogeneity of biomarkers in prostate cancer, a heterogeneity tissue microarray containing samples from 10 different tumor blocks of 190 large prostate cancers selected from a consecutive series of 480 radical prostatectomies was developed. ERG expression was analyzed by immunohistochemistry. Positive ERG immunostaining was found in arrayed cancer-containing samples from 103 of the 178 analyzable patients (58%). ERG immunostaining was homogeneously positive in 29 prostate cancers (16%), whereas heterogeneous ERG positivity was seen in 74 cancers (42%). ERG heterogeneity was within one tumor focus (intrafocal heterogeneity) in 69 cases (93% of heterogeneous cases) and between different tumor foci (interfocal heterogeneity) in 5 cases (7%). Marked intrafocal heterogeneity challenges the concept of TMPRSS2-ERG fusion always representing an early step in prostate cancer development. Marked heterogeneity also compromises the concept of analyzing ERG status for treatment decisions in diagnostic needle core biopsies. PMID:22899295

  5. Prostatitis - eine endlose Geschichte?

    Directory of Open Access Journals (Sweden)

    Riedl CR

    2001-01-01

    Full Text Available Aktuelle epidemiologische Daten aus den USA zeigen, daß der urogenitale Symptomenkomplex, der langläufig als "Prostatitis" bezeichnet wird, ein nicht unbeträchtliches volksgesundheitliches und volkswirtschaftliches Problem darstellt: dieses Krankheitsbild ist jährlich für 2 Millionen Arztbesuche und für 8% aller urologischen Konsulationen in den USA verantwortlich. Umgekehrt sieht jeder Urologe im Jahr zwischen 150 und 250 Patienten mit "Prostatitis".

  6. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue

    Directory of Open Access Journals (Sweden)

    Ribeiro Ricardo

    2012-09-01

    Full Text Available Abstract Background Periprostatic (PP adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW and prostate cancer patients. Methods Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia. Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA was used to investigate gene ontology, canonical pathways and functional networks. Results In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated. Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis, whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH. Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Conclusions Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable

  7. Bmi-1, stem cells and prostate carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    David Moscatelli; E Lynette Wilson

    2011-01-01

    @@ Malignant transformation is likely to arise in a subset of organ-specific primitive cells that are subverted to acquire the properties of uncontrolled self-renewal.1,2 It is therefore likely that stem cells and tumor-initiating cells share many properties and that an understanding of the biology of normal stem cells and the identification of the pathways and molecules that regulate their self-renewal may result in our ability to design inhibitors that control the growth of tumor cells.In an interesting recent paper, Lukacs et al.3 show that the polycomb group transcriptional repressor, Bmi-1, regulates the self-renewal of normal prostate stem cells and also contributes to the initiation of prostate cancer.

  8. Human RecQL4 helicase plays critical roles in prostate carcinogenesis

    DEFF Research Database (Denmark)

    Su, Yanrong; Meador, Jarah A; Calaf, Gloria M;

    2010-01-01

    Prostate cancer is the second leading cause of cancer-associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer-prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer c...... prostate cancer promotion. Observation of a direct interaction of retinoblastoma (Rb) and E2F1 proteins with RecQL4 promoter suggests that Rb-E2F1 pathway may regulate RecQL4 expression. Collectively, our study shows that RecQL4 is an essential factor for prostate carcinogenesis....

  9. Ezrin mediates c-Myc actions in prostate cancer cell invasion

    DEFF Research Database (Denmark)

    Chuan, Yin Choy; Iglesias-Gato, D; Fernandez-Perez, L;

    2010-01-01

    The forced overexpression of c-Myc in mouse prostate and in normal human prostate epithelial cells results in tumor transformation with an invasive phenotype. How c-Myc regulates cell invasion is poorly understood. In this study, we have investigated the interplay of c-Myc and androgens in the re...

  10. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  11. Drugs Approved for Prostate Cancer

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Prostate Cancer This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Prostate Cancer Abiraterone Acetate Bicalutamide Cabazitaxel Casodex (Bicalutamide) Degarelix Docetaxel ...

  12. Understanding Prostate Cancer: Newly Diagnosed

    Science.gov (United States)

    ... Wellness PCF Spotlight Glossary African American Men Understanding Prostate Cancer Newly Diagnosed Newly Diagnosed Staging the Disease Issues ... you care about has recently been diagnosed with prostate cancer, this section will help guide you through the ...

  13. Molecular genetic, diagnosis, prevention and gene therapy in prostatic cancer: review article

    Directory of Open Access Journals (Sweden)

    Noori Daloii MR

    2009-04-01

    Full Text Available "nThe prostate is a small gland located below the bladder and upper part of the urethra. In developed countries prostate cancer is the second common cancer (after skin cancer, and also the second leading cause of cancer death (after lung cancer among men. The several studies have been shown prostate cancer familial aggregation. The main reason for this aggregation is inheritance included genes. The family history is an important risk factor for developing the disease. The genes AR, CYP17, SRD5A2, HSD3B1 and HSD3B2 are all intimately involved in androgen metabolism and cell proliferation in the prostate. Each shows intraspecific polymorphism and variation among racial-ethnic groups that is associated with the risk of prostate cancer. Some of genes expressed in the prostate are in association with the production of seminal fluid and also with prostate cancer. Epigenetic modifications, specifically DNA hypermethylation, are believed to play an important role in the down-regulation of genes important for protection against prostate cancer. In prostate cancer numerous molecular and genetic aberrations have been described. It is now well established that cancer cells exhibit a number of genetic defects in apoptotic pathways. In this review article, the most recent data in molecular genetic, prevention and especially gene therapy in prostate cancer are introduced.

  14. Prostate cancer epigenetics and its clinical implications

    Directory of Open Access Journals (Sweden)

    Srinivasan Yegnasubramanian

    2016-01-01

    Full Text Available Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  15. Prostate cancer epigenetics and its clinical implications.

    Science.gov (United States)

    Yegnasubramanian, Srinivasan

    2016-01-01

    Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy. PMID:27212125

  16. Effect of magnesium oxide on interfraction prostate motion and rectal filling in prostate cancer radiotherapy. Analysis of a randomized clinical trial

    International Nuclear Information System (INIS)

    To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during radiotherapy for prostate cancer. From December 2008 to February 2010, 92 prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. In a previous study, we investigated the effect on intrafraction motion and did not find a difference between the treatment arms. Here, we compared the interfraction prostate motion between the two treatment arms as well as the amount of rectal filling and rectal air pockets using pretreatment planning computed tomography and magnetic resonance imaging scans. There was no statistically significant difference between the treatment arms in translation and rotation of the prostate between treatment fractions, except for the rotation around the cranial caudal axis. However, the difference was less than 1 and therefore considered not clinically relevant. There was no significant difference in the amount of rectal filling and rectal air pockets between the treatment arms. Magnesium oxide is not effective in reducing the interfraction prostate motion or the amount of rectal filling and rectal gas during external-beam radiotherapy. Therefore, magnesium oxide is not recommended in clinical practice for these purposes. (orig.)

  17. Methods for Prostate Biopsy

    Directory of Open Access Journals (Sweden)

    M. Ghafoori

    2008-01-01

    Full Text Available Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-specific antigen (PSA test is among the best screening tools available in medicine today and is recognized as the best marker for its early detection. Prostate cancers detected by DRE method alone are clinically localized only 50% to 60% of the time, whereas PSA-detected tumors are clinically localized 90% of the time and pathologi-cally confined to the prostate as determined at prostatectomy about two thirds of the time. Recently, the detection of localized prostate cancers has improved, owing to the development of various new biopsy methods. However, a standard biopsy method, including number of cores, has not yet been established at present. When screening results indi-cate the possibility of prostate cancer, a pathologic diagnosis may be pursued by ultrasound guided trans-rectal needle biopsy. Prostate biopsy is usually ad-vised if serum PSA is >4 ng/mL, and this procedure remains the gold standard for prostate cancer diagno-sis. Fine needle biopsy is less painful than core bi-opsy, but also less diagnostically accurate. Systematic biopsy protocols: In 1989, Hodge et al. coined the sextant biopsy method that is still the standard of reference in prostate cancer detection. The prostate is bilaterally divided into three regions (apex, midgland, and base, all of which are system-atically biopsied once. Although Hodge et al. first proposed sextant biopsy under transrectal ultrasound guidance, some recent reports have indicated that systematic sextant biopsy

  18. Genetic epidemiology of prostate cancer

    OpenAIRE

    Wiklund, Fredrik

    2004-01-01

    Prostate cancer is a major health burden throughout the world, yet the etiology of prostate cancer is poorly understood. Evidence has accumulated supporting the existence of a hereditary form of this disease. Improved understanding of the genetic mechanisms underlying the development and progression of prostate cancer would be a major advance for improved prevention, detection and treatment strategies. This thesis evaluates different aspects of the genetic epidemiology of prostate cancer. In ...

  19. Prostate cancer: emerging pharmacotherapeutic modalities

    OpenAIRE

    Pratap Shankar; Anoop Kumar Verma; Rakesh Kumar Dixit; Amod Kumar Sachan

    2013-01-01

    Prostate cancer is the most common cancer in the world due to factors like old age, family history, ethnicity, diet and some elements exposure, with lot of controversies regarding prevention of prostate cancer. Though the exact pathogenesis is not clear, epidemiological evidence supports a relationship between prostate cancer and hormone levels. In this review article we are focusing on the advances in different pharmacotherapeutic modalities i.e. Chemoprevention, Prostate-Specific Antigen, H...

  20. Focal therapy in prostate cancer

    OpenAIRE

    Bos, van den, G.A.M.

    2016-01-01

    Interesting developments took place in the treatment of prostate cancer including focal therapy for less aggressive organ-confined prostate cancer. Fortunately, curative treatment is often still an option for patients suffering from the lower staged tumors. In carefully selected patients, the prostate cancer may be focally treated followed by careful post-treatment evaluation, and if necessary by focal re-treatment. During the past decades, the age of men at prostate cancer detection has decr...

  1. BPH and prostate cancer risk

    OpenAIRE

    Miah, Saiful; Catto, James

    2014-01-01

    Introduction: With the exclusion of non-melanomatous skin malignancy, prostate cancer (PCa) is the second most prevalent cancer in men globally. It has been reported that the majority of men will develop benign prostatic hyperplasia (BPH) by the time they reach their 60s. Together, these prostatic diseases have a significant morbidity and mortality affecting over a billion men throughout the world. The risk of developing prostate cancer of men suffering BPH is one that has resulted in a healt...

  2. Metastaze raka prostate u penis

    OpenAIRE

    Krpina, Kristian; Markić, Dean; Španjol, Josip; Valenčić, Maksim; Fučkar, Željko

    2011-01-01

    Metastaziranje adenokarcinoma prostate u penis je rijetko. Prikazuje se slučaj adenokarcinoma prostate s metastazama u glans penis. U ovom slučaju metastaze u penis razvile su se devet godina nakon dijagnosticiranja raka prostate s metastazama u regionalne limfne čvorove.

  3. Cholesterol and benign prostate disease.

    Science.gov (United States)

    Freeman, Michael R; Solomon, Keith R

    2011-01-01

    The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept. PMID:21862201

  4. Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia

    NARCIS (Netherlands)

    Robert, G.Y.M.; Smit, F.; Hessels, D.; Jannink, S.A.; Karthaus, H.F.M.; Aalders, T.; Jansen, K.; Taille, A. De La; Mulders, P.F.A.; Schalken, J.A.

    2011-01-01

    BACKGROUND: Chronic prostatic inflammation could be a central mechanism in benign prostatic hyperplasia (BPH) progression. Currently, the histological examination of prostate biopsies remains the only way to diagnose prostatic inflammation. Our objective was to find new noninvasive biomarkers for th

  5. Steroid hormone receptors in prostatic hyperplasia and prostatic carcinoma.

    Science.gov (United States)

    Khalid, B A; Nurshireen, A; Rashidah, M; Zainal, B Y; Roslan, B A; Mahamooth, Z

    1990-06-01

    One hundred and six prostatic tissue samples obtained from transurethral resection were analysed for androgen and estrogen receptors. In 62 of these, progesterone and glucocorticoid receptors were also assayed. Steroid receptors were assayed using single saturation dose 3H-labelled ligand assays. Ninety percent of the 97 prostatic hyperplasia tissues and six of the nine prostatic carcinoma tissues were positive for androgen receptors. Estrogen receptors were only present in 19% and 33% respectively. Progesterone receptors were present in 70% of the tissues, but glucocorticoid receptors were present in only 16% of prostatic hyperplasia and none in prostatic carcinoma. PMID:1725553

  6. Characterization of SV-40 Tag rats as a model to study prostate cancer

    Directory of Open Access Journals (Sweden)

    Eltoum Isam A

    2009-01-01

    Full Text Available Abstract Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1 signaling proteins in the novel SV-40 Tag rat. Methods The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA kits. Results Prostatic intraepithelial neoplasia (PIN and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP followed by in the dorsolateral (DLP. At 8 weeks of age, testosterone and dihydrotestosterone (DHT concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. Conclusion The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of

  7. Characterization of SV-40 Tag rats as a model to study prostate cancer

    International Nuclear Information System (INIS)

    Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of

  8. The link between benign prostatic hyperplasia and prostate cancer

    DEFF Research Database (Denmark)

    Ørsted, David Dynnes; Bojesen, Stig E

    2013-01-01

    Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen...... therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological...... studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH as a...

  9. Three axis attitude control system

    Science.gov (United States)

    Studer, Philip A. (Inventor)

    1988-01-01

    A three-axis attitude control system for an orbiting body comprised of a motor driven flywheel supported by a torque producing active magnetic bearing is described. Free rotation of the flywheel is provided about its central axis and together with limited angular torsional deflections of the flywheel about two orthogonal axes which are perpendicular to the central axis. The motor comprises an electronically commutated DC motor, while the magnetic bearing comprises a radially servoed permanent magnet biased magnetic bearing capable of producing cross-axis torques on the flywheel. Three body attitude sensors for pitch, yaw and roll generate respective command signals along three mutually orthogonal axes (x, y, z) which are coupled to circuit means for energizing a set of control coils for producing torques about two of the axes (x and y) and speed control of the flywheel about the third (z) axis. An energy recovery system, which is operative during motor deceleration, is also included which permits the use of a high-speed motor to perform effectively as a reactive wheel suspended in the magnetic bearing.

  10. SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

    DEFF Research Database (Denmark)

    Iglesias Gato, Diego; Chuan, Yin Choy; Wikström, Pernilla;

    2014-01-01

    Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2) a...

  11. CAND1 Promotes PLK4-Mediated Centriole Overduplication and Is Frequently Disrupted in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Nina Korzeniewski

    2012-09-01

    Full Text Available Centrosomes play a crucial role in the maintenance of genome stability by orchestrating bipolar mitotic spindle formation. The centrosome normally duplicates precisely once before mitosis in a process that is extensively regulated by protein degradation including SKP1-Cullin 1 (CUL1-F-box (SCF E3 ubiquitin ligase activity. The core SCF component CUL1 has recently been found to be required to suppress the formation of supernumerary centrosomes and centrioles, the core-forming units of centrosomes. Here, we identify the CUL1-interacting protein cullin-associated and neddylation-dissociated 1 (CAND1 as a novel centrosomal protein with a role in centriole duplication control. CAND1 was found to synergize with Polo-like kinase 4 (PLK4, a master regulator of centriole biogenesis, in the induction of centriole overduplication. We provide evidence that CAND1 functions in this process by increasing PLK4 protein stability. Furthermore, mutants of CUL1 that lack the ability to interact with CAND1 and are unable to assemble functional E3 ubiquitin ligase complexes were impaired in their ability to restrain aberrant daughter centriole synthesis. To corroborate a role of CAND1 in human carcinogenesis, we analyzed a series of prostate adenocarcinomas and found altered expression of CAND1 on the mRNA or protein level in 52.9% and 40.8%, respectively, of the tumor samples analyzed. These results highlight the role of altered SCF components in cancer in general and encourage further studies to explore the SCF-CAND1 axis for the development of novel predictive biomarkers and therapeutic approaches in prostate cancer.

  12. XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Li Chunde

    2010-12-01

    Full Text Available Abstract Background Somatostatin prevents cell proliferation by inducing apoptosis. Downregulation of the XAF1 transcript may occur during the development of prostate cancer. It is interesting to evaluate the potential regulatory effects of somatostatin on XAF1 expression during the development of prostate cancer cells. Methods XAF1 mRNA and protein expression in human prostate epithelial cells RWPE-1, androgen dependent prostate cancer LNCaP, and androgen independent DU145 and PC3 cells were evaluated using RT-PCR and Western blot. The regulation of XAF1 mRNA and protein expression by somatostatin and its analogue Octreotide was evaluated. Results Substantial levels of XAF1 mRNA and proteins were detected in RWPE-1 cells, whereas prostate cancer cells LNCaP, DU145 and PC3 exhibited lower XAF1 expression. Somatostatin and Octreotide up-regulated XAF1 mRNA and protein expression in all prostate cancer cell lines. Conclusions XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy.

  13. Easy axis switching in magnetite

    International Nuclear Information System (INIS)

    The easy magnetic axis switching in magnetite is investigated. Magnetization data confirmed activation character of the process with activation energy of the same order as that of the Verwey transition, suggesting common origin. On the other hand this activation energy rises with pressure (up to 1.2GPa), unlike TV. The axis switching is clearly reflected in field dependence of resistivity and the direct structural data showed that it is simultaneous with the reorganization of structure. Thus, control of the structure can be possible with the application of magnetic field, as in shape memory materials. Finally, NMR showed that all, possibly decoupled entities: lattice distortion and charge and orbital orderings, change simultaneously while the axis switching occurs.

  14. Vertical axis wind turbine airfoil

    Science.gov (United States)

    Krivcov, Vladimir; Krivospitski, Vladimir; Maksimov, Vasili; Halstead, Richard; Grahov, Jurij Vasiljevich

    2012-12-18

    A vertical axis wind turbine airfoil is described. The wind turbine airfoil can include a leading edge, a trailing edge, an upper curved surface, a lower curved surface, and a centerline running between the upper surface and the lower surface and from the leading edge to the trailing edge. The airfoil can be configured so that the distance between the centerline and the upper surface is the same as the distance between the centerline and the lower surface at all points along the length of the airfoil. A plurality of such airfoils can be included in a vertical axis wind turbine. These airfoils can be vertically disposed and can rotate about a vertical axis.

  15. Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

    Directory of Open Access Journals (Sweden)

    Uddhav P. Kelavkar

    2006-06-01

    Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

  16. Osteoporosis and prostate cancer

    DEFF Research Database (Denmark)

    Poulsen, Mads Hvid; Nielsen, Morten Frost Munk; Abrahamsen, Bo;

    2014-01-01

    Abstract Objective. The aim of this study was to analyse the prevalence of osteoporosis and risk factors of osteoporotic fractures before androgen deprivation in Danish men. Treatment and prognosis of prostate cancer necessitate management of long-term consequences of androgen deprivation therapy...... (ADT), including accelerated bone loss resulting in osteoporosis. Osteoporotic fractures are associated with excess morbidity and mortality. Material and methods. Patients with prostate cancer awaiting initiation of ADT were consecutively included. Half of the patients had localized disease and were......-specific antigen level was 30.5 g/l (1-5714 g/l). The average Gleason score was 7.8 (range 5-10, SD 1.1). Fifty patients had localized prostate cancer and the other 55 patients had disseminated disease. The prevalence of osteoporosis was 10% and the prevalence of osteopenia was 58% before ADT. There was no...

  17. Clinical Perspective of Prostate Cancer.

    Science.gov (United States)

    Patil, Nilesh; Gaitonde, Krishnanath

    2016-06-01

    Prostate cancer is the most common noncutaneous cancer affecting men today. It largely affects men in the fifth and sixth decade of life. Screening for prostate cancer, though controversial, is still the only way to detect early prostate cancer. Multiple newer options such as blood tests and genetic markers are being used in the clinical domain today to improve cancer detection and avoid unnecessary biopsies. To date, biopsy of the prostate remains the only modality to stratify the grade of cancer. Significant improvements in the imaging technology have improved localizing and detecting the disease. Treatment of prostate cancer is stratified on the basis of the grade and volume of the disease. There are multiple treatment options involved in the management of prostate cancer. Treatment of localized prostate cancer still continues to have very high cure rates and long-term cancer-specific survival rates. PMID:27187167

  18. Two-axis angular effector

    International Nuclear Information System (INIS)

    A new class of coplanar two-axis angular effectors is described. These effectors combine a two-axis rotational joint analogous to a Cardan joint with linear actuators in a manner to produce a wider range of rotational motion about both axes defined by the joint. This new class of effectors also allows design of robotic manipulators having very high strength and efficiency. These effectors are particularly suited for remote operation in unknown surroundings, because of their extraordinary versatility. An immediate application is to the problems which arise in nuclear waste remediation. 11 figs

  19. Helical axis stellarator equilibrium model

    International Nuclear Information System (INIS)

    An asymptotic model is developed to study MHD equilibria in toroidal systems with a helical magnetic axis. Using a characteristic coordinate system based on the vacuum field lines, the equilibrium problem is reduced to a two-dimensional generalized partial differential equation of the Grad-Shafranov type. A stellarator-expansion free-boundary equilibrium code is modified to solve the helical-axis equations. The expansion model is used to predict the equilibrium properties of Asperators NP-3 and NP-4. Numerically determined flux surfaces, magnetic well, transform, and shear are presented. The equilibria show a toroidal Shafranov shift

  20. Chemotherapy in Prostate Cancer.

    Science.gov (United States)

    Hurwitz, Michael

    2015-10-01

    For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics. PMID:26216506

  1. Prostate Cancer Research Trial Helps John Spencer Treat His Cancer

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Prostate Cancer Research Trial Helps John Spencer Treat His ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  2. Benign Prostatic Hyperstatic Hyperplasia (BPH) (Beyond the Basics)

    Science.gov (United States)

    ... names for benign prostatic hyperplasia include benign prostatic hypertrophy, an enlarged prostate, and BPH. BPH occurs only ... prostatic hyperplasia" .) Alpha blockers — These medications relax the muscle of the prostate and bladder neck, which allows ...

  3. Long term organ culture of human prostate tissue in a NASA-designed rotating wall bioreactor

    Science.gov (United States)

    Margolis, L.; Hatfill, S.; Chuaqui, R.; Vocke, C.; Emmert-Buck, M.; Linehan, W. M.; Duray, P. H.

    1999-01-01

    PURPOSE: To maintain ex vivo integral prostatic tissue including intact stromal and ductal elements using the NASA-designed Rotating Wall Vessel (RWV) which maintains colocalized cells in an environment that promotes both three-dimensional cellular interactions together with the uniform mass transfer of nutrients and metabolic wastes. MATERIALS AND METHODS: Samples of normal prostate were obtained as a byproduct of transurethral prostatectomy or needle biopsy. Prostatic tissue dissected into small 1 x 1 mm. blocks was cultured in the Rotating Wall Vessel (RWV) Bioreactor for various time periods and analyzed using histological, immunochemical, and total cell RNA assays. RESULTS: We report the long term maintenance of benign explanted human prostate tissue grown in simple culture medium, under the simulated microgravity conditions afforded by the RWV bioreactor. Mesenchymal stromal elements including blood vessels and architecturally preserved tubuloglandular acini were maintained for a minimum of 28 days. Cytokeratins, vimentin and TGF-beta2 receptor and ligand were preserved through the entire culture period as revealed by immunocytochemistry. Prostatic acid phosphatase (PAP) was continuously expressed during the culture period, although somewhat decreased. Prostatic specific antigen (PSA) and its transcript were down regulated over time of culture. Prostatic carcinoma cells from the TSU cell line were able to invade RWV-cultured benign prostate tissue explants. CONCLUSIONS: The RWV bioreactor represents an additional new technology for culturing prostate tissue for further investigations concerning the basic physiology and pathobiology of this clinically important tissue.

  4. Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population.

    Science.gov (United States)

    Luk, Sze-Ue; Lee, Terence Kin-Wah; Liu, Ji; Lee, Davy Tak-Wing; Chiu, Yung-Tuen; Ma, Stephanie; Ng, Irene Oi-Lin; Wong, Yong-Chuan; Chan, Franky Leung; Ling, Ming-Tat

    2011-01-01

    Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer. PMID:21603625

  5. Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1.

    Science.gov (United States)

    Fuhrman-Luck, Ruth A; Stansfield, Scott H; Stephens, Carson R; Loessner, Daniela; Clements, Judith A

    2016-08-01

    Prostate cancer metastasis to bone is terminal; thus, novel therapies are required to prevent end-stage disease. Kallikrein-related peptidase 4 (KLK4) is a serine protease that is overproduced in localized prostate cancer and is abundant in prostate cancer bone metastases. In vitro, KLK4 induces tumor-promoting phenotypes; however, the underlying proteolytic mechanism is undefined. The protein topography and migration analysis platform (PROTOMAP) was used for high-depth identification of KLK4 substrates secreted by prostate cancer bone metastasis-derived PC-3 cells to delineate the mechanism of KLK4 action in advanced prostate cancer. Thirty-six putative novel substrates were determined from the PROTOMAP analysis. In addition, KLK4 cleaved the established substrate, urokinase-type plasminogen activator, thus validating the approach. KLK4 activated matrix metalloproteinase-1 (MMP1), a protease that promotes prostate tumor growth and metastasis. MMP1 was produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site. KLK4 further liberated an N-terminal product, with purported angiogenic activity, from thrombospondin-1 (TSP1) and cleaved TSP1 in an osteoblast-derived matrix. This is the most comprehensive analysis of the proteolytic action of KLK4 in an advanced prostate cancer model to date, highlighting KLK4 as a potential multifunctional regulator of prostate cancer progression. PMID:27378148

  6. Nonprostatic sources of prostate-specific antigen.

    Science.gov (United States)

    Diamandis, E P; Yu, H

    1997-05-01

    The name prostate-specific antigen has been given to a protein that now is known not to be prostate-specific; however, prostatic tissue does produces extremely high levels of PSA and secrets it into the seminal plasma. Seminal plasma contains about 1 million micrograms/L of PSA and is the richest source of PSA reported. The biologic fluid with the second highest PSA concentration, however, is nipple aspirate fluid from the female breast (up to about 5000 micrograms/L), and the third is milk from lactating women (up to 300 micrograms/L). Male serum PSA is usually less than 4 micrograms/L. In nonprostatic tissues, PSA exists mainly in its free molecular form, but PSA-ACT complex is also present in most of the fluids that contain PSA, such as breast secretions and amniotic fluid. The gene expression and protein production of PSA in nonprostatic tissues are under the regulation of steroid hormones via their receptors. Androgens, glucocorticoids, and progestins up-regulate the PSA gene expression, resulting in an increase of protein production. Estrogen by itself seems to have no effect on PSA regulation, but it can impair PSA production induced by androgen. It remains unknown whether PSA is enzymatically active and what is the physiologic role of PSA in nonprostatic tissues. It is speculated that PSA may be involved in the regulation of growth factors. Measuring PSA in breast cancer cytosol, breast-nipple aspirate fluid, and female serum may have potential clinical utilities, including breast cancer prognosis, breast cancer risk assessment, and evaluation of androgen excess. Further studies are needed to identify the exact function and regulation of PSA in nonprostatic tissues and to explore the clinical application of this protein. PMID:9126224

  7. Survival in prostate cancer prevention trial detailed

    Science.gov (United States)

    In the NCI-sponsored Prostate Cancer Prevention Trial, initial findings from a decade ago showed that the drug finasteride significantly reduced the risk of prostate cancer, but among those who did develop prostate cancer, paradoxically, the drug was asso

  8. Prostate Cancer Rates by Race and Ethnicity

    Science.gov (United States)

    ... HPV-Associated Lung Ovarian Skin Uterine Cancer Home Prostate Cancer Rates by Race and Ethnicity Language: English Español ( ... Tweet Share Compartir The rate of men getting prostate cancer or dying from prostate cancer varies by race ...

  9. Prostate Cancer: Take Time to Decide

    Science.gov (United States)

    ... PDF for professional printing [PDF-983KB] Cancer Home Prostate Cancer: Take Time to Decide Infographic Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Prostate Cancer: Take Time to Decide Most prostate cancers grow ...

  10. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P;

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...

  11. Detecting Prostate Cancer

    Medline Plus

    Full Text Available Roger Babaian, M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled and ... testing may be required. Physician: OK, what I'd like to do is just do a rectal ...

  12. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... an abnormality in their rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they ... tissue with a needle. Physician: Now there's a little pressure -- you can probably feel that. Then you' ...

  13. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P; Christensen, I; Denis, L

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...

  14. Common Questions About Chronic Prostatitis.

    Science.gov (United States)

    Holt, James D; Garrett, W Allan; McCurry, Tyler K; Teichman, Joel M H

    2016-02-15

    Chronic prostatitis is relatively common, with a lifetime prevalence of 1.8% to 8.2%. Risk factors include conditions that facilitate introduction of bacteria into the urethra and prostate (which also predispose the patient to urinary tract infections) and conditions that can lead to chronic neuropathic pain. Chronic prostatitis must be differentiated from other causes of chronic pelvic pain, such as interstitial cystitis/bladder pain syndrome and pelvic floor dysfunction; prostate and bladder cancers; benign prostatic hyperplasia; urolithiasis; and other causes of dysuria, urinary frequency, and nocturia. The National Institutes of Health divides prostatitis into four syndromes: acute bacterial prostatitis, chronic bacterial prostatitis (CBP), chronic nonbacterial prostatitis (CNP)/chronic pelvic pain syndrome (CPPS), and asymptomatic inflammatory prostatitis. CBP and CNP/CPPS both lead to pelvic pain and lower urinary tract symptoms. CBP presents as recurrent urinary tract infections with the same organism identified on repeated cultures; it responds to a prolonged course of an antibiotic that adequately penetrates the prostate, if the urine culture suggests sensitivity. If four to six weeks of antibiotic therapy is effective but symptoms recur, another course may be prescribed, perhaps in combination with alpha blockers or nonopioid analgesics. CNP/CPPS, accounting for more than 90% of chronic prostatitis cases, presents as prostatic pain lasting at least three months without consistent culture results. Weak evidence supports the use of alpha blockers, pain medications, and a four- to six-week course of antibiotics for the treatment of CNP/CPPS. Patients may also be referred to a psychologist experienced in managing chronic pain. Experts on this condition recommend a combination of treatments tailored to the patient's phenotypic presentation. Urology referral should be considered when appropriate treatment is ineffective. Additional treatments include pelvic

  15. Prostate brachytherapy in patients with prior evidence of prostatitis

    International Nuclear Information System (INIS)

    Purpose: To refute a misconception that a prior history of prostatitis is a contraindication to prostate brachytherapy. Methods and Materials: Five patients with clinical or pathologic evidence of prior prostatitis were treated with transperineal brachytherapy. Four of the patients received a single i.v. dose of ciprofloxacin (500 mg) intraoperatively. Postimplant antibiotics were not given. The pretreatment biopsy slides were reviewed. Results: Two of the five patients developed postimplant urinary retention requiring short-term catheterization, and both resolved spontaneously. One patient developed what appeared to be an exacerbation of his chronic prostatitis. Conclusion: We continue to recommend prostate brachytherapy for the treatment of clinically organ-confined cancer, with no concern about prior clinical or pathologic evidence of prostatitis

  16. KCTD11 Tumor Suppressor Gene Expression Is Reduced in Prostate Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Francesca Zazzeroni

    2014-01-01

    Full Text Available Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified. KCTD11 (REN is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh signaling. Here, we demonstrated that KCTD11 LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels of KCTD11 mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers.

  17. KCTD11 tumor suppressor gene expression is reduced in prostate adenocarcinoma.

    Science.gov (United States)

    Zazzeroni, Francesca; Nicosia, Daniela; Tessitore, Alessandra; Gallo, Rita; Verzella, Daniela; Fischietti, Mariafausta; Vecchiotti, Davide; Ventura, Luca; Capece, Daria; Gulino, Alberto; Alesse, Edoardo

    2014-01-01

    Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH) of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified. KCTD11 (REN) is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh) signaling. Here, we demonstrated that KCTD11 LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels of KCTD11 mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers. PMID:25045667

  18. Periostin identified as a potential biomarker of prostate cancer by iTRAQ-proteomics analysis of prostate biopsy

    Directory of Open Access Journals (Sweden)

    Tong Shijun

    2011-04-01

    Full Text Available Abstract Background Proteomics may help us better understand the changes of multiple proteins involved in oncogenesis and progression of prostate cancer(PCa and identify more diagnostic and prognostic biomarkers. The aim of this study was to screen biomarkers of PCa by the proteomics analysis using isobaric tags for relative and absolute quantification(iTRAQ. Methods The patients undergoing prostate biopsies were classified into 3 groups according to pathological results: benign prostate hyperplasia (BPH, n = 20, PCa(n = 20 and BPH with local prostatic intraepithelial neoplasm(PIN, n = 10. Then, all the specimens from these patients were analyzed by iTRAQ and two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS. The Gene Ontology(GO function and the transcription regulation networks of the differentially expressed were analyzed by MetaCore software. Western blotting and Immunohistochemical staining were used to analyze the interesting proteins. Result A total of 760 proteins were identified from 13787 distinct peptides, including two common proteins that enjoy clinical application: prostate specific antigen (PSA and prostatic acid phosphatase(PAP. Proteins that expressed differentially between PCa and BPH group were further analyzed. Compared with BPH, 20 proteins were significantly differentially up-regulated (>1.5-fold while 26 were significantly down-regulated in PCa( Conclusion Our study indicates that the iTRAQ technology is a new strategy for global proteomics analysis of the tissues of PCa. A significant up-regulation of periostin in PCa compared to BPH may provide clues for not only a promising biomarker for the prognosis of PCa but also a potential target for therapeutical intervention.

  19. Epigenetic inactivation of inhibitor of differentiation 4 (Id4) correlates with prostate cancer

    International Nuclear Information System (INIS)

    The inhibitor of DNA-binding (Id) proteins, Id1–4 are negative regulators of basic helix-loop-helix (bHLH) transcription factors. As key regulators of cell cycle and differentiation, expression of Id proteins are increasingly observed in many cancers and associated with aggressiveness of the disease. Of all the four Id proteins, the expression of Id1, Id2, and to a lesser extent, Id3 in prostate cancer and the underlying molecular mechanism is relatively well known. On the contrary, our previous results demonstrated that Id4 acts as a potential tumor suppressor in prostate cancer. In the present study, we extend these observations and demonstrate that Id4 is down-regulated in prostate cancer due to promoter hypermethylation. We used prostate cancer tissue microarrays to investigate Id4 expression. Methylation specific PCR on bisulfite treated DNA was used to determine methylation status of Id4 promoter in laser capture micro-dissected normal, stroma and prostate cancer regions. High Id4 expression was observed in the normal prostate epithelial cells. In prostate cancer, a stage-dependent decrease in Id4 expression was observed with majority of high grade cancers showing no Id4 expression. Furthermore, Id4 expression progressively decreased in prostate cancer cell line LNCaP and with no expression in androgen-insensitive LNCaP-C81 cell line. Conversely, Id4 promoter hypermethylation increased in LNCaP-C81 cells suggesting epigenetic silencing. In prostate cancer samples, loss of Id4 expression was also associated with promoter hypermethylation. Our results demonstrate loss of Id4 expression in prostate cancer due to promoter hypermethylation. The data strongly support the role of Id4 as a tumor suppressor

  20. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Steven Kregel

    Full Text Available Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR, has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5 expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

  1. MRI diagnosis for prostate cancer

    International Nuclear Information System (INIS)

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  2. MRI diagnosis for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao (Kawasaki Medical School, Kurashiki, Okayama (Japan)); Matsuki, Takakazu

    1998-01-01

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  3. MRI diagnosis for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Tsutomu; Nagai, Kiyohisa; Imai, Shigeki; Kajihara, Yasumasa; Jo, Yoshimasa; Tanaka, Hiroyoshi; Fukunaga, Masao [Kawasaki Medical School, Kurashiki, Okayama (Japan); Matsuki, Takakazu

    1998-12-31

    Recently, in Japan, both the Westernization of life styles and the advent of an aged-society have led to an increase in the incidence of prostate cancer. In making a localizing diagnosis of prostate cancer, magnetic resonance imaging (MRI), which has excellent contrast resolution, and transrectal ultrasonography, are used clinically, and their usefulness is being established. MRI is employed in the diagnosis of prostate cancer to detect tumors, and to determine the stage of such tumors. For the visualization of prostate cancer by MRI, T2-weighted axial images are used exclusively. After becoming familiar with normal prostate images, it is important to evaluate the localization of a tumor, and the invasion of the capsule and seminal vesicles. Future applications of new techniques for MRI will undoubtedly be found. In this paper, the present state of MRI diagnosis of prostate cancer at Kawasaki Medical School Hospital will be reviewed. (author)

  4. Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

    OpenAIRE

    Drake, JM; Paull, EO; Graham, NA; Lee, JK; Smith, BA; Titz, B; Stoyanova, T; Faltermeier, CM; Uzunangelov, V; Carlin,, R.; Fleming, DT; Wong, CK; Newton, Y; Sudha, S; Vashisht, AA

    2016-01-01

    We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of drugga...

  5. Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer

    DEFF Research Database (Denmark)

    Sørensen, Karina Dalsgaard; Abildgaard, Mette Opstrup; Haldrup, Christa;

    2013-01-01

    Background:Novel biomarkers for prostate cancer (PC) are urgently needed. This study investigates the expression, epigenetic regulation, and prognostic potential of ANPEP in PC.Methods:Aminopeptidase N (APN; encoded by ANPEP) expression was analysed by immunohistochemistry using tissue microarrays...

  6. Vertical axis wind turbine acoustics

    OpenAIRE

    Pearson, Charlie

    2014-01-01

    Increasing awareness of the issues of climate change and sustainable energy use has led to growing levels of interest in small-scale, decentralised power generation. Small-scale wind power has seen significant growth in the last ten years, partly due to the political support for renewable energy and the introduction of Feed In Tariffs, which pay home owners for generating their own electricity. Due to their ability to respond quickly to changing wind conditions, small-scale vertical axis...

  7. BENIGN PROSTATIC HYPERPLASIA: UPDATED REVIEW

    OpenAIRE

    Praveen.R

    2013-01-01

    Benign Prostatic Hyperplasia (BPH) is one of the commonest medical conditions affecting the geriatric male population. The enlargement of prostate can lead to various clinical symptoms like difficulty in voiding, urinary retention etc. The symptoms are varied depending on the size of enlargement. The International Prostatic Symptom Score (IPSS) is the gold standard and first step in understanding and diagnosing the disease clinically, but in the recent past there are various other newer tools...

  8. Culture of mouse prostate organoids

    OpenAIRE

    sprotocols

    2014-01-01

    Authors: Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, LaMont Barlow & Michael Shen ### Abstract This protocol describes a novel three-dimensional “organoid” culture for prostate epithelial cells. We describe the digestion and dissociation of prostate tissue into single-cell suspensions containing both prostatic epithelial and stromal cells, the isolation of epithelial cells from the parental population via fluorescence activated cell sorting, and the plating condition...

  9. Prevention strategies in prostate cancer

    OpenAIRE

    Trottier, Greg; Lawrentschuk, N.; Fleshner, N.E.

    2010-01-01

    Prostate cancer (pca) prevention has been an exciting and controversial topic since the results of the Prostate Cancer Prevention Trial (pcpt) were published. With the recently published results of the reduce (Reduction by Dutasteride of Prostate Cancer Events) trial, interest in this topic is at a peak. Primary pca prevention will be unlikely to affect mortality significantly, but the reduction in overtreatment and the effect on quality of life from the avoidance of a cancer diagnosis are im...

  10. Prostatic Stromal Hyperplasia with Atypia

    OpenAIRE

    Hutchinson, Ryan C.; Wu, Kevin J.; Cheville, John C.; Thiel, David D

    2013-01-01

    Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and revie...

  11. Prostatic Stromal Hyperplasia with Atypia

    Directory of Open Access Journals (Sweden)

    Ryan C. Hutchinson

    2013-01-01

    Full Text Available Prostatic stromal hyperplasia with atypia (PSHA is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding.

  12. Neuroendocrine aspects of prostate oncogenesis

    Directory of Open Access Journals (Sweden)

    P.V. Glybochko

    2010-03-01

    Full Text Available The prostate cancer is a widespread disease in Russia with high growth rate and high death rate. Active work in discovery of methods of early diagnostics of prostate cancer is carrying out. it will allow to increase considerably the efficiency of treatment. the data on topography, structural and functional organization, physiology and regulatory effect of neuroendocrine cells and neuroendocrine hormones and peptides of prostate produced by neuroendocrine cells are presented in the review. Neuroendocrine mechanisms of development, prospects of early diagnostics and prognosis of prostate cancer are analyzed

  13. Spin-axis pointing of a magnetically actuated spacecraft

    Science.gov (United States)

    Avanzini, G.; de Angelis, E. L.; Giulietti, F.

    2014-01-01

    Attitude regulation proves to be a challenging problem, when magnetic actuators alone are used as attitude effectors, since they do not provide three independent control torque components at each time instant. In this paper a rigorous proof of global exponential stability is derived for a magnetic control law that leads the satellite to a desired spin condition around a principal axis of inertia, pointing the spin axis toward a prescribed direction in the inertial frame. The technique is demonstrated by means of numerical simulation of a few example maneuvers. An extensive Monte Carlo simulation is performed for random initial conditions, in order to investigate the effect of changes in control law gains.

  14. The development of a compact positron tomograph for prostate imaging

    Energy Technology Data Exchange (ETDEWEB)

    Huber, Jennifer S.; Qi, Jinyi; Derenzo, Stephen E.; Moses, William W.; Huesman, Ronald H.; Budinger, Thomas F.

    2002-12-17

    We give design details and expected image results of a compact positron tomograph designed for prostate imaging that centers a patient between a pair of external curved detector banks (ellipse: 45 cm minor, 70 cm major axis). The bottom bank is fixed below the patient bed, and the top bank moves upward for patient access and downward for maximum sensitivity. Each bank is composed of two rows (axially) of 20 CTI PET Systems HR+ block detectors, forming two arcs that can be tilted to minimize attenuation. Compared to a conventional PET system, our camera uses about one-quarter the number of detectors and has almost two times higher solid angle coverage for a central point source, because the detectors are close to the patient. The detectors are read out by modified CTI HRRT data acquisition electronics. The individual detectors are angled in the plane to point towards the prostate to minimize reso

  15. miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.

    Directory of Open Access Journals (Sweden)

    Cyrielle Clapé

    Full Text Available BACKGROUND: Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. RESULTS: Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5 activity. We show here that ERK5 is a miR-143 target in prostate cancer. CONCLUSIONS: miR-143 is as a new target for prostate cancer treatment.

  16. Acupuncture Treatment of Prostatitis

    Institute of Scientific and Technical Information of China (English)

    HU Jin-sheng

    2010-01-01

    @@ MEDICAL HISTORY A male patient, aged 78, a Hong Kong resident, paid his first visit on October 15, 2007. He complained of frequent urination, 5-6 times at night and once every hour during the daytime, and often with urgent urination and urinary incontinence in the previous 10 months. The patient had been diagnosed by a local hospital as having prostatitis and hyperplasia of the prostate, and he had coronary heart disease treated with Aspirin and other western medicines. As he was getting older, he felt deficient stamina, lassitude, lumbago, feeble lower limbs, pain in the left thigh with restricted motion, preference of local warmness, normal appetite, and powerless defecation once every other day. However, the patient was open-minded with good mental state.

  17. Association of Symptomatic Benign Prostatic Hyperplasia and Prostate Cancer: Results from the Prostate Cancer Prevention Trial

    OpenAIRE

    Schenk, Jeannette M.; Kristal, Alan R.; Arnold, Kathryn B.; Tangen, Catherine M.; Neuhouser, Marian L; Lin, Daniel W; White, Emily; Thompson, Ian M

    2011-01-01

    This study examined the association between symptomatic benign prostatic hyperplasia (BPH) and prostate cancer risk in 5,068 placebo-arm participants enrolled in the Prostate Cancer Prevention Trial (1993–2003). These data include 1,225 men whose cancer was detected during the 7-year trial—556 detected for cause (following abnormal prostate-specific antigen or digital rectal examination) and 669 detected not for cause (without indication), as well as 3,843 men who had biopsy-proven absence of...

  18. Predictive value of prostate-specific antigen for prostate cancer

    DEFF Research Database (Denmark)

    Shepherd, Leah; Borges, Alvaro Humberto; Ravn, Lene;

    2014-01-01

    INTRODUCTION: Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV- men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV- men. We aimed to describe the kinetics and...

  19. The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer

    DEFF Research Database (Denmark)

    Iversen, Peter; Roder, Martin Andreas; Røder, Martin Andreas

    2008-01-01

    The Early Prostate Cancer program is investigating the addition of bicalutamide 150 mg to standard care for localized or locally advanced, nonmetastatic prostate cancer. The third program analysis, at 7.4 years' median follow-up, has shown that bicalutamide 150 mg does not benefit patients with...

  20. Prostate Cancer: All Aspects

    OpenAIRE

    Ahmet Tefekli; Murat Tunc; Volkan Tugcu; Tarık Esen

    2013-01-01

    Hindawi Publishing Corporation The ScientificWorld Journal Volume 2013, Article ID 265234, 2 pages http://dx.doi.org/10.1155/2013/265234 Editorial Prostate Cancer: All Aspects Ahmet Tefekli,1 Murat Tunc,2 Volkan Tugcu,3 and TarJk Esen4 1 Bahcesehir School of Medicine, 34353 Istanbul, Turkey 2 Istanbul School of Medicine, Istanbul University, 34340 Istanbul, Turkey 3Department of Urology, Bakırkoy Training and Research Hospital, 34360 Istanbul, Turkey 4 Koc Univer...

  1. Prostate Focused Ultrasound Therapy.

    Science.gov (United States)

    Chapelon, Jean-Yves; Rouvière, Olivier; Crouzet, Sébastien; Gelet, Albert

    2016-01-01

    The tremendous progress in engineering and computing power coupled with ultrasound transducer technology and imaging modalities over the past 20 years have encouraged a revival of clinical interest in ultrasound therapy, mainly in High-Intensity Focused Ultrasound (HIFU). So far, the most extensive results from HIFU obtained in urology involve transrectal prostate ablation, which appears to be an effective therapeutic alternative for patients with malignant prostate tumors. Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men. Several treatment options with different therapeutic approaches exist, including HIFU for localized PCa that has been in use for over 15 years. Since the early 2000s, two systems have been marketed for this application, and other devices are currently in clinical trials. HIFU treatment can be used either alone or in combination with (before- or after-) external beam radiotherapy (EBRT) (before or after HIFU) and can be repeated multiple times. HIFU treatment is performed under real-time monitoring with ultrasound or guided by MRI. Two indications are validated today: Primary care treatment and EBRT failure. The results of HIFU for primary care treatment are similar to standard conformal EBRT, even though no randomized comparative studies have been performed and no 10-year follow up data is yet available for HIFU. Salvage HIFU after EBRT failure is increasing with oncological outcomes, similar to those achieved with surgery but with the advantage of fewer adverse effects. HIFU is an evolving technology perfectly adapted for focal treatment. Thus, HIFU focal therapy is another pathway that must be explored when considering the accuracy and reliability for PCa mapping techniques. HIFU would be particularly suited for such a therapy since it is clear that HIFU outcomes and toxicity are relative to the volume of prostate treated. PMID:26486330

  2. Prostate cancer brachytherapy

    International Nuclear Information System (INIS)

    The transperineal brachytherapy with 125I/Pd103 seed implantation guided by transurethral ultrasound must be presented as therapeutical option of low urinary morbidity in patients with localized prostate cancer. The combined clinical staging - including Gleason and initial PSA - must be encouraged, for definition of a group of low risk and indication of exclusive brachytherapy. Random prospective studies are necessary in order to define the best role of brachytherapy, surgery and external beam radiation therapy

  3. Genistein chemoprevention of prostate cancer in TRAMP mice

    Directory of Open Access Journals (Sweden)

    Eltoum Isam-Eldin

    2007-01-01

    Full Text Available Abstract Epidemiological studies suggest an inverse association between soy intake and prostate cancer risk. Genistein, the predominant phytoestrogen in soy food, has been proposed as a potential chemopreventive agent due to its anti-estrogen and tyrosine kinase inhibitory effects. To determine the most effective period for genistein chemoprevention, the Transgenic adenocarcinoma mouse prostate (TRAMP model was used. The treatments were 250 mg genistein/kg AIN-76A diet 1 prepubertally only, 2 in adulthood only or 3 through out life. Controls received AIN-76A diet. By 28 weeks of age, 100% TRAMP mice fed control diet developed prostatic intraepithelial neoplasia (PIN or adenocarcinomas with 6%, 16%, 44% and 34% developing high grade PIN, well differentiated, moderately differentiated and poorly differentiated prostatic adenocarcinomas, respectively. Prepubertal only (1–35 days postpartum and adult only genistein treatments (12 – 28 weeks resulted in 6% and 29% decreases in poorly-differentiated cancerous lesions compared with controls, respectively. The most significant effect was seen in the TRAMP mice exposed to genistein throughout life (1–28 weeks with a 50% decrease in poorly-differentiated cancerous lesions. In a separate experiment in castrated TRAMP mice, dietary genistein suppressed the development of advanced prostate cancer by 35% compared with controls. Of the tumors that developed in castrated TRAMP mice, 100% were poorly-differentiated in contrast to the 37% of noncastrated TRAMP mice that developed poorly-differentiated tumors. ICI 182,780 (ICI, genistein and estrogen down-regulated androgen receptor (AR, estrogen receptor alpha (ER-α and progesterone receptor (PR in the prostates of C57BL/6 mice, and act independently of ER. Our data obtained in intact and castrated transgenic mice suggest that genistein may be a promising chemopreventive agent against androgen-dependent and independent prostate cancers.

  4. Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells.

    Science.gov (United States)

    Lowe, S L; Rubinchik, S; Honda, T; McDonnell, T J; Dong, J Y; Norris, J S

    2001-09-01

    In prostate carcinoma, overexpression of the anti-apoptotic gene Bcl-2 has been found to be associated with resistance to therapies including radiation and androgen ablation. Restoring the balance of Bcl-2 family members may result in the induction of apoptosis in prostate cancer cells previously resistant to treatment. To accomplish this, a strategy involving overexpression of the pro-apoptotic gene Bax was executed. The use of cytotoxic genes such as Bax require selective expression of the gene. In this study, we examined the ability of selective expression of Bax protein directed by a prostate-specific promoter to induce apoptosis in human prostate carcinoma. A second-generation adenoviral vector was constructed with the modified prostate-specific probasin promoter, ARR2PB, directing expression of an HA-tagged Bax gene and a green fluorescent protein reporter translated from an internal ribosome entry site (ARR2PB.Bax.GFP). ARR2PB promoter activity is tightly regulated and highly prostate specific and is responsive to androgens and glucocorticoids. The prostate-specific promoter-Bax-GFP transgene cassette was inserted into a cloning site near the right inverted terminal repeat of the adenoviral vector to retain specificity of the promoter. LNCaP cells infected with Ad/ARR(2)PB.Bax.GFP showed high levels of Bax expression 48 h after infection resulting in an 85% reduction in cell viability. Importantly, LNCaP cells stably transfected to overexpress Bcl-2 showed similar patterns of cell death when infected with Ad/ARR(2)PB.Bax.GFP, an 82% reduction in cell viability seen 48 h after infection. Apoptosis was confirmed by measuring caspase activation and using the TUNEL assay. Tissue specificity was evaluated using A549 cells (lung adenocarcinoma), SK-Hep-1 (liver cancer) cells, and Hela (cervical cancer) cells which did not show detectable expression of virally delivered Bax protein or any increase in cell death. Systemic administration of Ad/ARR2PB. Bax.GFP in nude

  5. Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats.

    Science.gov (United States)

    Kuno, Toshiya; Nagano, Aya; Mori, Yukiko; Kato, Hiroyuki; Nagayasu, Yuko; Naiki-Ito, Aya; Suzuki, Shugo; Mori, Hideki; Takahashi, Satoru

    2016-01-01

    Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP) strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172) was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer. PMID:27409632

  6. Effects of cisplatin on the LSD1-mediated invasion and metastasis of prostate cancer cells.

    Science.gov (United States)

    Chen, Zhi-Yuan; Chen, Hui; Qiu, Tao; Weng, Xiao-Dong; Guo, Jia; Wang, Lei; Liu, Xiu-Heng

    2016-09-01

    Prostate cancer poses a major public health problem in men. Metastatic prostate cancer is incurable, and ultimately threatens the life of patients. Lysine‑specific demethylase 1 (LSD1) is an androgen receptor‑interacting protein that exerts a key role in regulating gene expression and is involved in numerous biological processes associated with prostate cancer. Cisplatin, also known as cis‑diamminedichloroplatinum or DDP, is a standard chemotherapeutic agent used to treat prostate cancer; however, it has the disadvantage of various serious side effects. The present study aimed to investigate the effects of LSD1 knockdown, and the interplay between LSD1 and DDP, on prostate cancer cell proliferation, apoptosis and invasion, and, therefore, the potential of LSD1 as a target for prostate cancer therapy. Flow cytometric analysis, Cell Counting kit 8 assay, Transwell assay and western blotting results revealed that LSD1 knockdown, in combination with DDP treatment, exerted antiproliferative, proapoptotic and anti‑invasive effects on PC3 prostate cancer cells. In addition, knockdown of LSD1 acted synergistically with DDP, thereby enhancing the induction of apoptosis, and the inhibition of proliferation and invasion in prostate cancer cells. These results indicated that LSD1 may serve as a potential therapeutic target, and may enhance the sensitivity of PC3 cells to DDP. PMID:27484796

  7. Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats

    Directory of Open Access Journals (Sweden)

    Toshiya Kuno

    2016-07-01

    Full Text Available Fermented brown rice and rice bran with Aspergillus oryzae (FBRA is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172 was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer.

  8. Embedded synaptic feedback in the neuroendocrine stress axis.

    Science.gov (United States)

    Wamsteeker Cusulin, J I; Bains, J S

    2015-06-01

    Neural regulation of blood glucocorticoid levels is critical for defence of homeostasis during physiological or psychoemotional challenges. In mammals, this function is carried out by the neuroendocrine stress axis, coordinated by parvocellular neuroendocrine cells (PNCs) of the paraventricular hypothalamic nucleus. Feedback regulation of PNCs by glucocorticoids provides complex experience-dependent shaping of neuroendocrine responses. We review recent evidence for metaplastic actions of glucocorticoids as 'circuit breakers' at synapses directly regulating PNC excitability and explore how such mechanisms may serve as substrates for stress adaptation. PMID:25612538

  9. β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Francis

    Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

  10. 3D transrectal ultrasound prostate biopsy using a mechanical imaging and needle-guidance system

    Science.gov (United States)

    Bax, Jeffrey; Cool, Derek; Gardi, Lori; Montreuil, Jacques; Gil, Elena; Bluvol, Jeremy; Knight, Kerry; Smith, David; Romagnoli, Cesare; Fenster, Aaron

    2008-03-01

    Prostate biopsy procedures are generally limited to 2D transrectal ultrasound (TRUS) imaging for biopsy needle guidance. This limitation results in needle position ambiguity and an insufficient record of biopsy core locations in cases of prostate re-biopsy. We have developed a multi-jointed mechanical device that supports a commercially available TRUS probe with an integrated needle guide for precision prostate biopsy. The device is fixed at the base, allowing the joints to be manually manipulated while fully supporting its weight throughout its full range of motion. Means are provided to track the needle trajectory and display this trajectory on a corresponding TRUS image. This allows the physician to aim the needle-guide at predefined targets within the prostate, providing true 3D navigation. The tracker has been designed for use with several end-fired transducers that can be rotated about the longitudinal axis of the probe to generate 3D images. The tracker reduces the variability associated with conventional hand-held probes, while preserving user familiarity and procedural workflow. In a prostate phantom, biopsy needles were guided to within 2 mm of their targets, and the 3D location of the biopsy core was accurate to within 3 mm. The 3D navigation system is validated in the presence of prostate motion in a preliminary patient study.

  11. Chemotherapeutic prevention studies of prostate cancer

    DEFF Research Database (Denmark)

    Djavan, Bob; Zlotta, Alexandre; Schulman, Claude;

    2004-01-01

    Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, ie the administration of agents that inhibit 1 or more steps in the natural...... history of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe....

  12. Prevention and early detection of prostate cancer

    NARCIS (Netherlands)

    Cuzick, J.; Thorat, M.A.; Andriole, G.; Brawley, O.W.; Brown, P.H.; Culig, Z.; Eeles, R.A.; Ford, L.G.; Hamdy, F.C.; Holmberg, L.; Ilic, D.; Key, T.J.; Vecchia, C. La; Lilja, H.; Marberger, M.; Meyskens, F.L.; Minasian, L.M.; Parker, C.; Parnes, H.L.; Perner, S.; Rittenhouse, H.; Schalken, J.A.; Schmid, H.P.; Schmitz-Drager, B.J.; Schroder, F.H.; Stenzl, A.; Tombal, B.; Wilt, T.J.; Wolk, A.

    2014-01-01

    Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-speci

  13. Chemotherapeutic prevention studies of prostate cancer

    DEFF Research Database (Denmark)

    Djavan, Bob; Zlotta, Alexandre; Schulman, Claude; Teillac, Pierre; Iversen, Peter; Boccon Gibod, Laurent; Bartsch, Georg; Marberger, Michael

    Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, ie the administration of agents that inhibit 1 or more steps in the natural...... history of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe....

  14. Survey of Differentially Methylated Promoters in Prostate Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Yipeng Wang

    2005-08-01

    Full Text Available DNA methylation, copy number in the genomes of three immortalized prostate epithelial, five cancer cell lines (LNCaP, PC3, PC3M, PC3M-Pro4, PC3MLN4 were compared using a microarray-based technique. Genomic DNA is cut with a methylation-sensitive enzyme Hpall, followed by linker ligation, polymerase chain reaction (PCR amplification, labeling, hybridization to an array of promoter sequences. Only those parts of the genomic DNA that have unmethylated restriction sites within a few hundred base pairs generate PCR products detectable on an array. Of 2732 promoter sequences on a test array, 504 (18.5% showed differential hybridization between immortalized prostate epithelial, cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, there were eight (CD44, CDKN1A, ESR1, PLAU, RARB, SFN, TNFRSF6, TSPY previously observed in prostate cancer, 13 previously known methylation targets in other cancers (ARHI, bcl-2, BRCA1, CDKN2C, GADD45A, MTAP, PGR, SLC26A4, SPARC, SYK, TJP2, UCHL1, WIT-1. The majority of genes that appear to be both differentially methylated, differentially regulated between prostate epithelial, cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, GG2-1, representing a rich new source of candidate genes used to study the role of DNA methylation in prostate tumors.

  15. Comparative Metabolomic and Lipidomic Analysis of Phenotype Stratified Prostate Cells.

    Directory of Open Access Journals (Sweden)

    Tanya C Burch

    Full Text Available Prostate cancer (PCa is the most prevalent cancer amongst men and the second most common cause of cancer related-deaths in the USA. Prostate cancer is a heterogeneous disease ranging from indolent asymptomatic cases to very aggressive life threatening forms. The goal of this study was to identify differentially expressed metabolites and lipids in prostate cells with different tumorigenic phenotypes. We have used mass spectrometry metabolomic profiling, lipidomic profiling, bioinformatic and statistical methods to identify, quantify and characterize differentially regulated molecules in five prostate derived cell lines. We have identified potentially interesting species of different lipid subclasses including phosphatidylcholines (PCs, phosphatidylethanolamines (PEs, glycerophosphoinositols (PIs and other metabolites that are significantly upregulated in prostate cancer cells derived from distant metastatic sites. Transcriptomic and biochemical analysis of key enzymes that are involved in lipid metabolism demonstrate the significant upregulation of choline kinase alpha in the metastatic cells compared to the non-malignant and non-metastatic cells. This suggests that different de novo lipogenesis and other specific signal transduction pathways are activated in aggressive metastatic cells as compared to normal and non-metastatic cells.

  16. HUMAN PROSTATE CANCER RISK FACTORS

    Science.gov (United States)

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  17. Human Prostate Cancer Hallmarks Map.

    Science.gov (United States)

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  18. ESUR prostate MR guidelines 2012

    DEFF Research Database (Denmark)

    Barentsz, Jelle O; Richenberg, Jonathan; Clements, Richard; Choyke, Peter; Verma, Sadhna; Villeirs, Geert; Rouviere, Olivier; Logager, Vibeke; Fütterer, Jurgen J

    2012-01-01

    The aim was to develop clinical guidelines for multi-parametric MRI of the prostate by a group of prostate MRI experts from the European Society of Urogenital Radiology (ESUR), based on literature evidence and consensus expert opinion. True evidence-based guidelines could not be formulated, but a...

  19. Vitamin E and Prostate Cancer

    Science.gov (United States)

    Vitamin E, its metabolites or its analogs, might help prevent prostate cancer initiation or progression. Prostate cancer is the most common non-skin malignancy and the second leading cause of cancer deaths among men in the United States, exceeded only by lung cancer. About 218,890 new cases of prost...

  20. Androgen Control in Prostate Cancer.

    Science.gov (United States)

    Pelekanou, Vasiliki; Castanas, Elias

    2016-10-01

    Research on prostate cancer has extensively advanced in the past decade, through an improved understanding for its genetic basis and risk-stratification. Molecular classification of prostate cancer into distinct subtypes and the recognition of new histologic entities promise the development of tailored-made management strategies of patients. Nowadays, various alternatives are available for clinical management of localized disease ranging from observation alone through radical prostatectomy. In patients with castration-resistant prostate cancer, the approval of new drugs for the management of metastatic disease has offered promising results improving the survival of these patients. In this context, androgen receptors (AR) remain at the epicenter of prostate cancer research holding a prominent role in the biology and therapeutic regimens of prostate cancer. As many of castration-resistant tumors retain hormone-responsiveness, AR is a clinical relevant, druggable target. However, AR paradoxically remains neglected as a prostate cancer biomarker. The great advancements in prostate cancer preclinical and clinical research, imply further improvement in clinical and translational data, for patient selection and treatment optimization. For a precision medicine-guided clinical management of prostate cancer, AR evaluation has to be implemented in companion and complementary diagnostics, as discussed here. J. Cell. Biochem. 117: 2224-2234, 2016. © 2016 Wiley Periodicals, Inc. PMID:27104784

  1. Expression of androgen receptor and prostate-specific antigen in male breast carcinoma

    International Nuclear Information System (INIS)

    The androgen-regulated proteins prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) are present in high concentrations in normal prostate and prostatic cancer and are considered to be tissue-specific to prostate. These markers are commonly used to diagnose metastatic prostate carcinoma at various sites including the male breast. However, expression of these two proteins in tumors arising in tissues regulated by androgens such as male breast carcinoma has not been thoroughly evaluated. In this study we analyzed the expression of PSA, PSAP and androgen receptor (AR) by immunohistochemistry in 26 cases of male breast carcinomas and correlated these with the expression of other prognostic markers. AR, PSA and PSAP expression was observed in 81%, 23% and 0% of carcinomas, respectively. Combined expression of AR and PSA was observed in only four tumors. Although the biological significance of PSA expression in male breast carcinomas is not clear, caution should be exercised when it is used as a diagnostic marker of metastatic prostate carcinoma

  2. Effect of Obesity on Prostate-Specific Antigen, Prostate Volume, and International Prostate Symptom Score in Patients with Benign Prostatic Hyperplasia

    OpenAIRE

    Kim, Jong Min; Song, Phil Hyun; Kim, Hyun Tae; Moon, Ki Hak

    2011-01-01

    Purpose We examined the correlation between body mass index (BMI) as a marker of obesity and prostate-specific antigen (PSA), prostate volume (PV), and International Prostate Symptom Score (IPSS) in patients with benign prostatic hyperplasia (BPH). Materials and Methods From January 2008 to December 2008, we examined 258 patients diagnosed with BPH. Patients taking 5α-reductase inhibitors or those diagnosed with prostate cancer were excluded from this study. BPH was defined as PV≥25 ml and IP...

  3. Comparison of telomerase activity in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic hyperplasia

    Directory of Open Access Journals (Sweden)

    Soleiman Mahjoub

    2006-11-01

    Full Text Available BACKGROUND: Telomerase is a reverse transcriptase enzyme that synthesizes telomeric DNA on chromosome ends. The enzyme is important for the immortalization of cancer cells because it maintains the telomeres. METHODS: Telomerase activity (TA was measured by fluorescence-based telomeric repeat amplification protocol (FTRAP assay in prostate carcinoma and benign prostatic hyperplasia (BPH. RESULTS: TA was present in 91.4% of 70 prostate cancers, 68.8% of 16 prostatic intraepithelial neoplasia (PIN, 43.3% of 30 BPH*, 21.4% of 14 atrophy and 20% of 15 normal samples adjacent to tumor. There was not any significant correlation between TA, histopathological tumor stage or gleason score. In contrast to high TA in the BPH* tissue from the cancer-bearing gland, only 6.3% of 32 BPH specimens from patients only diagnosed with BPH were telomerase activity-positive. CONCLUSIONS: These results indicate that TA is present in most prostate cancers. The high rate of TA in tissue adjacent to tumor may be attributed either to early molecular alteration of cancer that was histologically unapparent, or to the presence of occult cancer cells. Our findings suggest that the re-expression of telomerase activity could be one step in the transformation of BPH to PIN. KEY WORDS: Telomerase activity, prostate cancer, prostatic intraepithelial neoplasia, benign prostatic hyperplasia.

  4. The many ways to make a luminal cell and a prostate cancer cell

    Science.gov (United States)

    Strand, Douglas W; Goldstein, Andrew S

    2016-01-01

    Research in the area of stem/progenitor cells has led to the identification of multiple stem-like cell populations implicated in prostate homeostasis and cancer initiation. Given that there are multiple cells that can regenerate prostatic tissue and give rise to prostate cancer, our focus should shift to defining the signaling mechanisms that drive differentiation and progenitor self-renewal. In this article, we will review the literature, present the evidence and raise important unanswered questions that will help guide the field forward in dissecting critical mechanisms regulating stem-cell differentiation and tumor initiation. PMID:26307022

  5. Role of transurethral resection of the prostate in the management of prostate cancer

    OpenAIRE

    Szollosi Attila; Martha Orsolya; Denes Lorand; Vida Arpad Oliver; Maier Adrian; Pavai Zoltan

    2016-01-01

    Introduction: Prostate cancer is the second most diagnosed cancer in men, after lung cancer. The gold standard procedure in prostate cancer (PCa) diagnosis is the ultrasound guided prostate biopsy. Transurethral resection of the prostate (TURP) used in solving the bladder outlet obstruction, can have a role in detection of PCa. The aim of this retrospective study is to examine the role of transurethral resection of the prostate in the diagnosis and therapy of prostate cancer.

  6. Role of transurethral resection of the prostate in the management of prostate cancer

    Directory of Open Access Journals (Sweden)

    Szollosi Attila

    2016-06-01

    Full Text Available Introduction: Prostate cancer is the second most diagnosed cancer in men, after lung cancer. The gold standard procedure in prostate cancer (PCa diagnosis is the ultrasound guided prostate biopsy. Transurethral resection of the prostate (TURP used in solving the bladder outlet obstruction, can have a role in detection of PCa. The aim of this retrospective study is to examine the role of transurethral resection of the prostate in the diagnosis and therapy of prostate cancer.

  7. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    Directory of Open Access Journals (Sweden)

    Li-Juan Zhu

    Full Text Available Hypothalamus-pituitary-adrenal (HPA hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR - neuronal nitric oxide synthesis enzyme (nNOS - nitric oxide (NO pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  8. Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells.

    Science.gov (United States)

    Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K

    2011-10-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. PMID:21640721

  9. American Cancer Society Recommendations for Prostate Cancer Early Detection

    Science.gov (United States)

    ... saved articles window. My Saved Articles » My ACS » Prostate Cancer Prevention and Early Detection + - Text Size Download Printable Version [ ... coverage for prostate cancer screening Additional resources for prostate cancer prevention and early detection References: Prostate cancer prevention and ...

  10. A Prospective Randomized Trial of Two Different Prostate Biopsy Schemes

    Science.gov (United States)

    2016-07-03

    Prostate Cancer; Local Anesthesia; Prostate-Specific Antigen/Blood; Biopsy/Methods; Image-guided Biopsy/Methods; Prostatic Neoplasms/Diagnosis; Prostate/Pathology; Prospective Studies; Humans; Male; Ultrasonography, Interventional/Methods

  11. Radium-223 Improves Survival in Patients with Advanced Prostate Cancer

    Science.gov (United States)

    ... and data sets for researchers Research by Cancer Type Find research about a specific cancer type Progress Annual Report ... Laws Careers Visitor Information Search Search Home Cancer Types Prostate Cancer Research Prostate Cancer Patient Prostate Cancer Treatment Prostate Cancer ...

  12. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells.

    Science.gov (United States)

    Kashiwagi, Eiji; Shiota, Masaki; Yokomizo, Akira; Itsumi, Momoe; Inokuchi, Junichi; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer. PMID:23493387

  13. Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

    OpenAIRE

    Zhu, Meng-Lei; Horbinski, Craig; Garzotto, Mark; Qian, David Z.; Beer, Tomasz M.; Kyprianou, Natasha

    2010-01-01

    Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant-prostate cancer (CRPC), but the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling, and the consequences of their inhibit...

  14. Glutathione S-transferase Pi mediates proliferation of androgen-independent prostate cancer cells

    OpenAIRE

    Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki

    2008-01-01

    Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the ‘transgenic rat adenocarcinoma in prostate’ (TRAP) model, to analyze their gene expression using microarrays....

  15. Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer

    OpenAIRE

    Osamu Ogawa; Tomomi Kamba; Takahiro Inoue; Takashi Kobayashi

    2013-01-01

    In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent subli...

  16. Epidermal Growth Factor Increases LRF/Pokemon Expression in Human Prostate Cancer Cells

    OpenAIRE

    Aggarwal, Himanshu; Aggarwal, Anshu; Devendra K Agrawal

    2011-01-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that reg...

  17. Large scale phosphoproteome analysis of LNCaP human prostate cancer cells

    OpenAIRE

    Myung, Jae-Kyung; Sadar, Marianne D

    2012-01-01

    Prostate cancer is the most frequently diagnosed cancer among men in the western world. The androgen receptor, a phosphoprotein, is suspected to be involved in all stages of the prostate cancer. Androgen receptor activity can be modulated by various kinases such as PKA, MAPK, AKT, and Src. Phosphorylation is an important post-translational modification and serves as a molecular on/off switch to regulate signaling. Disruptions of cellular phosphorylation are associated with various diseases su...

  18. Blood Magnesium, and the Interaction with Calcium, on the Risk of High-Grade Prostate Cancer

    OpenAIRE

    Dai, Qi; Motley, Saundra S.; Smith, Joseph A.; Concepcion, Raoul; Barocas, Daniel; Byerly, Susan; Fowke, Jay H.

    2011-01-01

    Background Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk. Study Design In this biomarker sub-study of the Nashville Men's Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason≥7) and 100 low-grade cancer cases, 133 prostate intraepithe...

  19. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    OpenAIRE

    Rennie, Paul S.; Artem Cherkasov; Nada Lallous; Kush Dalal

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the ...

  20. A histological study of prostate

    Directory of Open Access Journals (Sweden)

    Ashfaq U. Hassan

    2013-08-01

    Full Text Available The work of anatomists and pathologists in the role of study of prostate has been significant. Starting from earlier times till modern time, the study of prostate has been a dynamic one and the basic anatomical knowledge of the prostate has undergone much change apart from the new techniques, micro invasive procedures and the chemotherapeutic approach for various disorders of the gland. The present study was based on the microscopic examination of Prostatic tissue of individuals with individual tissues of different age groups. The present study involved 40 cases which were further subdivided into various age groups and characteristic histological changes were noted. The study presents an assessment of age changes in prostate in elderly in Kashmiri population with pathological significance. Besides the histological study is of great importance in staging of diseases of prostate and especially in modern era where the incidence and prevalence of prostatic diseases is on rise. [Int J Res Med Sci 2013; 1(4.000: 557-562

  1. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  2. CSR1 suppresses tumor growth and metastasis of prostate cancer.

    Science.gov (United States)

    Yu, Guoying; Tseng, George C; Yu, Yan Ping; Gavel, Tim; Nelson, Joel; Wells, Alan; Michalopoulos, George; Kokkinakis, Demetrius; Luo, Jian-Hua

    2006-02-01

    Prostate cancer is frequent among men over 45 years of age, but it generally only becomes lethal with metastasis. In this study, we identified a gene called cellular stress response 1 (CSR1) that was frequently down-regulated and methylated in prostate cancer samples. Survival analysis indicated that methylation of the CSR1 promoter, and to a lesser extent down-regulation of CSR1 protein expression, was associated with a high rate of prostate cancer metastasis. Forced expression of CSR1 in prostate cancer cell lines DU145 and PC3 resulted in a two- to threefold decrease in colony formation and a 10-fold reduction in anchorage-independent growth. PC3 cells stably expressing CSR1 had an average threefold decrease in their ability to invade in vitro. Expression of CSR1 in PC3 cell xenografts produced a dramatic reduction (>8-fold) in tumor size, rate of invasion (0 versus 31%), and mortality (13 versus 100%). The present findings suggest that CSR1 is a potent tumor sup-pressor gene. PMID:16436673

  3. Abiraterone acetate for prostate cancer: a new era of hormonal therapies

    Institute of Scientific and Technical Information of China (English)

    Emmanuel S Antonarakis

    2011-01-01

    @@ Therapies targeting the androgen receptor (AR) axis have constituted the Holy Grail in the management of advanced prostate cancer for seven decades.1 These hormonal therapies have traditionally taken two main forms: those that suppress gonadal androgen synthesis (e.g.,the gonadotropin releasing hormone agonists/antagonists,such as leuprolide),and those that inhibit the AR directly (e.g.,the anti-androgens,such asbicalutamide).However,although the vast majority of patients with prostate cancer initially respond favorably to androgen-ablative therapies (manifested by tumor regressions and symptomatic improvements),all patients will eventually develop further disease progression after a median of 18-24 months.This transformed disease state,known as castration-resistant prostate cancer (CRPC),is invariably fatal.

  4. Analysis of the codon 72 polymorphism of TP53 and human papillomavirus infection in Iranian patients with prostate cancer.

    Science.gov (United States)

    Salehi, Zivar; Hadavi, Mahvash

    2012-09-01

    The TP53 gene is one of the most important tumor suppressor genes controlling DNA transcription and cell regulation. Common polymorphisms in p53 gene may play a role in some cancers. Some studies have reported an association between human papillomavirus (HPV) infections and prostate cancer. The aim of this study was to investigate whether the TP53 codon 72 polymorphism and HPV infection are responsible for susceptibility to prostate cancer in Iranian men. The prostate biopsies were taken during surgery from 68 Iranian prostatic cancer patients, and 85 patients with benign prostate hyperplasia. For genotyping of the p53 polymorphism at codon 72, PCRRFLP methods were used and the PCR products were digested with BstU1. An attempt was also made to detect HPV DNA in benign prostate hyperplasia and prostate cancer specimens. Among cancer cases, the distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes were 26.5%, 45.4%, and 19.1%, respectively. Among patients with benign prostate hyperplasia, the distribution of Arg/Arg, Arg/Pro, and Pro/Pro genotypes were 27%, 53%, and 20%, respectively. The allele frequencies did not differ significantly between prostate cancer and benign prostate hyperplasia samples. Human papillomavirus was detected only in three patients (4.4%; P = 0.71). The results from this study suggest that the TP53 codon 72 polymorphism and HPV infection do not confer susceptibility to prostate cancer in the Iranian population. Larger population-based studies are needed to clarify the relation between prostate carcinoma and p53 polymorphism and HPV infection. PMID:22825821

  5. Diagnostic imaging of the prostate

    International Nuclear Information System (INIS)

    Modalities for the diagnostic imaging of the prostate are surveyed. Transrectal sonography is thought to be the best method for the purpose, because of its non-invasive nature, fine picture quality, sufficient reproductivity and less expensive cost. Up-to-date utilizations of the method are described, such as diagnostic capability, staging, monitoring, screening and intervention. CT is less effective but MRI is promising to visualize internal structure inside the prostate. Two very new techniques, namely, ultrasonic Doppler color flow mapping and positron emission CT (PET), of which application to the prostate is being investigated originally in our laboratory, are introduced. (author) 100 refs

  6. A multiscale, mechanism-driven, dynamic model for the effects of 5α-reductase inhibition on prostate maintenance.

    Science.gov (United States)

    Zager, Michael G; Barton, Hugh A

    2012-01-01

    A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound

  7. A multiscale, mechanism-driven, dynamic model for the effects of 5α-reductase inhibition on prostate maintenance.

    Directory of Open Access Journals (Sweden)

    Michael G Zager

    Full Text Available A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T to the potent androgen 5α-dihydrotestosterone (DHT. This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer

  8. Prostate position relative to pelvic bony anatomy based on intraprostatic gold markers and electronic portal imaging

    International Nuclear Information System (INIS)

    Purpose: To describe the relative positions and motions of the prostate, pelvic bony anatomy, and intraprostatic gold fiducial markers during daily electronic portal localization of the prostate. Methods and Materials: Twenty prostate cancer patients were treated supine with definitive external radiotherapy according to an on-line target localization protocol using three or four intraprostatic gold fiducial markers and an electronic portal imaging device. Daily pretherapy and through-treatment electronic portal images (EPIs) were obtained for each of four treatment fields. The patients' pelvic bony anatomy, intraprostatic gold markers, and a best visual match to the target (i.e., prostate) were identified on simulation digitally reconstructed radiographs and during daily treatment setup and delivery. These data provided quantitative inter- and intrafractional analysis of prostate motion, its position relative to the bony anatomy, and the individual intraprostatic fiducial markers. Treatment planning margins, with and without on-line localization, were subsequently compared. Results: A total of 22,266 data points were obtained from daily pretherapy and through-treatment EPIs. The pretherapy three-dimensional (3D) average displacement of the fiducial markers, as a surrogate for the prostate, was 5.6 mm, which improved to 2.8 mm after use of the localization protocol. The bony anatomy 3D average displacement was 4.4 mm both before and after localization to the prostate (p = 0.46). Along the superior-inferior (SI), anterior-posterior (AP), and right-left (RL) axes, the average prostate displacement improved from 2.5, 3.7, and 1.9 mm, respectively, before localization to 1.4, 1.6, and 1.1 mm after (all p < 0.001). The pretherapy to through-treatment position of the bony landmarks worsened from 1.7 to 2.5 mm (p < 0.001) in the SI axis, remained statistically unchanged at 2.8 mm (p = 0.39) in the AP axis, and improved from 2.0 to 1.2 mm in the RL axis (p < 0.001). There

  9. Initial results of a positron tomograph for prostate imaging

    Energy Technology Data Exchange (ETDEWEB)

    Huber, J.S.; Choong, W.S.; Moses, W.W.; Qi, J.; Hu, J.; Wang,G.C.; Wilson, D.; Oh, S.; Huesman, R.H.; Derenzo, S.E.; Budinger, T.F.

    2004-11-29

    We present the status and initial images of a positrontomograph for prostate imaging that centers a patient between a pair ofexternal curved detector banks (ellipse: 45 cm minor, 70 cm major axis).The distance between detector banks adjusts to allow patient access andto position the detectors as closely as possible for maximum sensitivitywith patients of various sizes. Each bank is composed of two axial rowsof 20 CTI PET Systems HR+ block detectors for a total of 80 modules inthe camera. Compared to an ECAT HR PET system operating in 3D mode, ourcamera uses about one-quarter the number of detectors and hasapproximately the same sensitivity for a central point source, becauseour detectors are close to the patient. The individual detectors areangled in the plane to point towards the prostate to minimize resolutiondegradation in that region. The detectors are read out by modified CTIdata acquisition electronics. We have completed construction of thegantry and electronics, have developed detector calibration and dataacquisition software, and are taking coincidence data. We demonstratethat we can clearly visualize a "prostate" in a simple phantom.Reconstructed images of two phantoms are shown.

  10. MRI of prostate zonal anatomy with an endorectal surface coil

    International Nuclear Information System (INIS)

    The development of an endorectal surface coil now permits a partial study of the anatomical model developed by McNeal. Axial and coronal views, which were used to establish the model can be obtained in a short period of time with fast spin echo sequences. Axial views are performed along the proximal urethra and coronal views are performed along the axis of the distal urethra and the ejaculatory duts. Anatomical boundaries of the transitional zone are well delineated on axial views, illustrating the concept of 'inner gland'. The prostatic capsule and the neuro-vascular bundles, pathways of extension of the cancer out of the prostate are also well delineated. Coronal sections allow a very good anatomical study of the caudal junction of the vas deferens and the seminal vesicles (the so called weak space), pathway of tumor extension to the seminal vesicles. Differences in signal of the prostatic zones make the outer gland cancers very conspicuous as well as some transitional cancers which can show, in some cases, an homogeneous hyposignal. (authors). 15 refs., 14 figs

  11. Bouncing back - trauma and the HPA-axis in healthy adults

    Directory of Open Access Journals (Sweden)

    Ellen Renée Klaassens

    2010-12-01

    Full Text Available Dysregulation of the hypothalamic–pituitary–adrenal (HPA-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD. Some studies have reported HPA-axis dysregulation in trauma-exposed (TE adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology. Mentally healthy TE subjects were compared with non-trauma-exposed (NE healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH test. The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role.

  12. Oxidative stress in prostate hyperplasia and carcinogenesis.

    Science.gov (United States)

    Udensi, Udensi K; Tchounwou, Paul B

    2016-01-01

    Prostatic hyperplasia (PH) is a common urologic disease that affects mostly elderly men. PH can be classified as benign prostatic hyperplasia (BPH), or prostate cancer (PCa) based on its severity. Oxidative stress (OS) is known to influence the activities of inflammatory mediators and other cellular processes involved in the initiation, promotion and progression of human neoplasms including prostate cancer. Scientific evidence also suggests that micronutrient supplementation may restore the antioxidant status and hence improve the clinical outcomes for patients with BPH and PCa. This review highlights the recent studies on prostate hyperplasia and carcinogenesis, and examines the role of OS on the molecular pathology of prostate cancer progression and treatment. PMID:27609145

  13. Potassium channels in prostate and colonic cancer

    OpenAIRE

    Ousingsawat, Jiraporn

    2007-01-01

    Large conductance Ca2+-activated K+ channels in human prostate cancer The KCNMA1 gene encoding the alpha-subunit of BK channels is amplified and BK channel expression is enhanced in late-stage, metastatic and hormone-refractory human prostate cancer tissues, whereas benign prostate tissues show only a weak expression of BK channels. PC-3 hormone-insensitive prostate cancer cells, but not hormone-sensitive prostate cancer cells (LNCaP) and benign prostate hyperplasia cells (BPH-1), show an ...

  14. An unusually large leiomyoma of the prostate.

    Science.gov (United States)

    Kapp, Brian; Abarzua-Cabezas, Fernando; Cusano, Antonio; Meraney, Anoop

    2014-02-01

    Prostate leiomyomas are benign mesenchymal smooth muscle tumors devoid of glandular elements within the prostate or juxta-prostatic position. Leiomyomas develop in organs containing smooth muscle, including the kidney, bladder and seminal vesicle. Prostate leiomyomas are either a pure form or associated with benign prostate hyperplasia, and diagnosis is challenging, with definitive identification relying on pathology. However, imaging techniques, such as MRI, have proven to be useful diagnostic tools. We report on a 57-year-old male with lower urinary tract symptomatology who was diagnosed with a large prostate leiomyoma and underwent an open radical cystoprostatectomy and ileal conduit urinary diversion. PMID:24529022

  15. Prostate resonance imaging: morphology and metabolism

    International Nuclear Information System (INIS)

    The cancer of prostate is the most frequent neoplasms and the third cause of death in men, although the average of survival of patients it improved, the cancer of prostate is an important problem in health. The majority of these tumors are of slow growth and the early detection allows high probabilities of definitive treatment. The neoplasms of prostate detected at present are smaller than the detected ones 20 years ago behind, nevertheless exist big differences in the aggressiveness of these tumors. The images are very important in the management of prostate cancer, and the magnetic resonance imaging of the prostate is a new tool in the evaluation of prostate cancer

  16. 6 Common Cancers - Prostate Cancer

    Science.gov (United States)

    ... PSA tests. Read More "6 Common Cancers" Articles Lung Cancer / Breast Cancer / Prostate Cancer / Colorectal Cancer / Skin Cancer / Gynecologic Cancers Spring 2007 Issue: Volume 2 Number 2 Page 10 MedlinePlus | Subscribe | Magazine Information | Contact Us | Viewers & ...

  17. Neuroendocrine differentiation in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Jiaoti Huang

    2008-01-01

    @@ The treatment of choice for advanced/metastatic prostate cancer(PC) is hormonal therapy. Although patients respond initially to this therapy, the tumor will recur and enter the androgen-independent state, which is the major obstacle in therapy.

  18. Prostate resection - minimally invasive - discharge

    Science.gov (United States)

    ... a burning sensation when you urinate, fever, or chills). Your urine stream is not as strong, or ... pubmed/23234640 . Roehrborn CG. Benign prostatic hyperplasia: Etiology, pathophysiology, epidemiology, and natural history. In: Wein AJ, Kavoussi ...

  19. Contemporary Management of Prostate Cancer.

    Science.gov (United States)

    Cotter, Katherine; Konety, Badrinath; Ordonez, Maria A

    2016-01-01

    Prostate cancer represents a spectrum ranging from low-grade, localized tumors to devastating metastatic disease. We discuss the general options for treatment and recent developments in the field. PMID:26949522

  20. Multidrug Resistance in Prostate Cancer

    NARCIS (Netherlands)

    J.P. van Brussel

    2005-01-01

    textabstractAdvanced hormone refractory prostate cancer constitutes a therapeutic challenge, because all available treatment strategies have failed to substantially increase cancer specific survival. Among these strategies, a multitude of chemotherapeutic approaches did not offer a superior life

  1. Treatment Option Overview (Prostate Cancer)

    Science.gov (United States)

    ... This procedure is done to treat benign prostatic hypertrophy and it is sometimes done to relieve symptoms ... or part of the small intestine through weak muscles into the groin ). Inguinal hernia may occur more ...

  2. The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer.

    Science.gov (United States)

    Shen, Hui; Powers, Nathan; Saini, Nitin; Comstock, Clay E S; Sharma, Ankur; Weaver, Katherine; Revelo, Monica P; Gerald, William; Williams, Erin; Jessen, Walter J; Aronow, Bruce J; Rosson, Gary; Weissman, Bernard; Muchardt, Christian; Yaniv, Moshe; Knudsen, Karen E

    2008-12-15

    Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm-/- epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen-induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer. PMID:19074882

  3. PEBP4 silencing inhibits hypoxia-induced epithelial-to-mesenchymal transition in prostate cancer cells.

    Science.gov (United States)

    Li, Weiping; Dong, Yongchao; Zhang, Bin; Kang, Yindong; Yang, Xukai; Wang, He

    2016-07-01

    Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Phosphatidylethanolamine-binding protein 4 (PEBP4) is a member of the PEBP family and has been reported to be upregulated in various cancer types. The definite function of PEBP4 in regulating the EMT of prostate cancer, however, is still unclear. Here, we examined the functional role of PEBP4 and the underlying molecular mechanisms in hypoxia-induced EMT in prostate cancer cells. Our results showed that PEBP4 mRNA and protein expression was markedly increased in the human prostate cancer tissues and cell lines. Knockdown of PEBP4 significantly inhibited hypoxia-induced migration/invasion and EMT program. Furthermore, knockdown of PEBP4 prevented hypoxia-induced the expression of p-Akt and p-mTOR in prostate cancer cells. Taken together, this study reported here provided evidence that knockdown of PEBP4 inhibited hypoxia-induced EMT in prostate cancer cells. Our study uncovered a novel role for PEBP4 in prostate cancer progression, which might support the potential for PEBP4 targeting in prostate cancer therapy. PMID:27261570

  4. Rectal function following prostate brachytherapy

    International Nuclear Information System (INIS)

    Purpose: Quality of life following therapeutic intervention for carcinoma of the prostate gland has not been well documented. In particular, a paucity of data has been published regarding bowel function following prostate brachytherapy. This study evaluated late bowel function in 209 consecutive prostate brachytherapy patients via a one-time questionnaire administered 16-55 months postimplant. Materials and Methods: Two hundred nineteen consecutive patients underwent permanent prostate brachytherapy from April 1995 through February 1998 using either 125I or 103Pd for clinical T1c-T3a carcinoma of the prostate gland. Of the 219 patients, 7 had expired. Of the remaining 212 patients (median follow-up, 28 months), each patient was mailed a self-administered questionnaire (10 questions) with a prestamped return envelope; 209 (98.6%) surveys were returned. Clinical parameters evaluated for bowel dysfunction included patient age, diabetes, hypertension, history of tobacco consumption, clinical T-stage, elapsed time since implant, and prostate ultrasound volume. Treatment parameters included utilization of neoadjuvant hormonal manipulation, utilization of moderate dose external beam radiation therapy prior to implantation, choice of isotope (125I vs. 103Pd), rectal dose (average, median and maximum doses), total implanted seed strength, values of the minimum dose received by 90% of the prostate gland (D90), and the percent prostate volume receiving 100%, 150%, and 200% of the prescribed minimum peripheral dose (V100, V150 and V200, respectively). Because detailed baseline bowel function was not available for these patients, a cross-sectional survey was performed in which 30 newly diagnosed prostate cancer patients of comparable demographics served as controls. Results: The total rectal function scores for the brachytherapy and control patients were 4.3 and 1.6, respectively, out of a total 27 points (p 103Pd resulted in lower radiation doses to the rectum, the choice of

  5. Microbiota and the gut-brain axis.

    Science.gov (United States)

    Bienenstock, John; Kunze, Wolfgang; Forsythe, Paul

    2015-08-01

    Changes in gut microbiota can modulate the peripheral and central nervous systems, resulting in altered brain functioning, and suggesting the existence of a microbiota gut-brain axis. Diet can also change the profile of gut microbiota and, thereby, behavior. Effects of bacteria on the nervous system cannot be disassociated from effects on the immune system since the two are in constant bidirectional communication. While the composition of the gut microbiota varies greatly among individuals, alterations to the balance and content of common gut microbes may affect the production of molecules such as neurotransmitters, e.g., gamma amino butyric acid, and the products of fermentation, e.g., the short chain fatty acids butyrate, propionate, and acetate. Short chain fatty acids, which are pleomorphic, especially butyrate, positively influence host metabolism by promoting glucose and energy homeostasis, regulating immune responses and epithelial cell growth, and promoting the functioning of the central and peripheral nervous systems. In the future, the composition, diversity, and function of specific probiotics, coupled with similar, more detailed knowledge about gut microbiota, will potentially help in developing more effective diet- and drug-based therapies. PMID:26175487

  6. Prostate cancer stem cell biology

    OpenAIRE

    Yu, Chunyan; Yao, Zhi; Jiang, Yuan; Keller, Evan T.

    2012-01-01

    The cancer stem cell (CSC) model provides insights into pathophysiology of cancers and their therapeutic response. The CSC model has been both controversial, yet provides a foundation to explore cancer biology. In this review, we provide an overview of CSC concepts, biology and potential therapeutic avenues. We then focus on prostate CSC including (1) their purported origin as either basal-derived or luminal-derived cells; (2) markers used for prostate CSC identification; (3) alterations of s...

  7. Perceived causes of prostate cancer among prostate cancer survivors in the Netherlands

    NARCIS (Netherlands)

    Kok, D.E.G.; Cremers, R.G.H.M.; Aben, K.K.H.; Oort, van I.M.; Kampman, E.; Kiemeney, L.A.L.M.

    2013-01-01

    Introduction The aim of this study was to evaluate self-reported causes of prostate cancer among prostate cancer survivors in the Netherlands to obtain insight into the common beliefs and perceptions of risk factors for prostate cancer. Materials and methods A total of 956 prostate cancer survivors,

  8. Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues

    Directory of Open Access Journals (Sweden)

    Franklin Renty B

    2006-04-01

    Full Text Available Abstract Background In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. Results The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. Conclusion The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells

  9. The Role of “Mixed” Orexigenic and Anorexigenic Signals and Autoantibodies Reacting with Appetite-Regulating Neuropeptides and Peptides of the Adipose Tissue-Gut-Brain Axis: Relevance to Food Intake and Nutritional Status in Patients with Anorexia Nervosa and Bulimia Nervosa

    Directory of Open Access Journals (Sweden)

    Kvido Smitka

    2013-01-01

    Full Text Available Eating disorders such as anorexia (AN and bulimia nervosa (BN are characterized by abnormal eating behavior. The essential aspect of AN is that the individual refuses to maintain a minimal normal body weight. The main features of BN are binge eating and inappropriate compensatory methods to prevent weight gain. The gut-brain-adipose tissue (AT peptides and neutralizing autoantibodies play an important role in the regulation of eating behavior and growth hormone release. The mechanisms for controlling food intake involve an interplay between gut, brain, and AT. Parasympathetic, sympathetic, and serotoninergic systems are required for communication between brain satiety centre, gut, and AT. These neuronal circuits include neuropeptides ghrelin, neuropeptide Y (NPY, peptide YY (PYY, cholecystokinin (CCK, leptin, putative anorexigen obestatin, monoamines dopamine, norepinephrine (NE, serotonin, and neutralizing autoantibodies. This extensive and detailed report reviews data that demonstrate that hunger-satiety signals play an important role in the pathogenesis of eating disorders. Neuroendocrine dysregulations of the AT-gut-brain axis peptides and neutralizing autoantibodies may result in AN and BN. The circulating autoantibodies can be purified and used as pharmacological tools in AN and BN. Further research is required to investigate the orexigenic/anorexigenic synthetic analogs and monoclonal antibodies for potential treatment of eating disorders in clinical practice.

  10. Prostatic Artery Embolization for Enlarged Prostates Due to Benign Prostatic Hyperplasia. How I Do It

    Energy Technology Data Exchange (ETDEWEB)

    Carnevale, Francisco C., E-mail: fcarnevale@uol.com.br [University of Sao Paulo Medical School, Interventional Radiology Unit (Brazil); Antunes, Alberto A., E-mail: antunesuro@uol.com.br [University of Sao Paulo Medical School, Division of Urology (Brazil)

    2013-12-15

    Prostatic artery embolization (PAE) has emerged as an alternative to surgical treatments for benign prostatic hyperplasia (BPH). Patient selection and refined technique are essential for good results. Urodynamic evaluation and magnetic resonance imaging are very important and technical limitations are related to elderly patients with tortuous and atherosclerotic vessels, anatomical variations, difficulty visualizing and catheterizing small diameter arteries feeding the prostate, and the potential risk of bladder and rectum ischemia. The use of small-diameter hydrophilic microcatheters is mandatory. Patients can be treated safely by PAE with low rates of side effects, reducing prostate volume with clinical symptoms and quality of life improvement without urinary incontinence, ejaculatory disorders, or erectile dysfunction. A multidisciplinary approach with urologists and interventional radiologists is essential to achieve better results.

  11. Developing imaging strategies for castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR-targeted drugs. Methods. We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results. The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for 'radiographic' progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na18F-PET for imaging of bone metastases is still uncertain. FDG-PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as 18F-FDHT and 89Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions. Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential to

  12. Percutaneous prostatic arterial embolization for the treatment of benign prostatic hyperplasia

    International Nuclear Information System (INIS)

    Percutaneous prostatic artery embolization (PAE) is a kind of technology that can treat benign prostatic hyperplasia through embolizing bilateral prostatic arteries to obstruct most blood supply to the prostate thus to cause prostatic tissue necrosis and the volume reduction of the prostate, resulting in the improvement of the clinical symptoms. This technique is technically simple, clinically convenient and well repeatable. This article aims to make a special comment about the history of PAE, the blood supply of the prostate, the indications and contraindications of the technique, the operative procedure, the complications and limitations, etc. (authors)

  13. Hybrid Registration of Prostate and Seminal Vesicles for Image Guided Radiation Therapy

    International Nuclear Information System (INIS)

    Purpose: Fiducial markers are a good surrogate for the prostate but provide little information on the position and orientation of the seminal vesicles (SVs). Therefore, a more advanced localization method is warranted if the SVs are part of the target volume. The purpose of this study was to develop a hybrid registration technique for the localization of the prostate and SVs. Methods and Materials: Twenty prostate patients implanted with 2 or 3 elongated fiducial markers had cone beam computed tomography (CBCT) scans acquired at every fraction. The first step of the hybrid registration was to localize the prostate by CBCT-to-planning-CT alignment of the fiducial markers, allowing both translations and rotations. Using this marker registration as a starting point, the SVs were registered based on gray values, allowing only rotations around the lateral axis. We analyzed the differential rotation between the prostate and SVs and compared the required SV margins for 3 correction strategies. Results: The SV registration had a precision of 2.7° (1 standard deviation) and was successful for 96% of the scans. Mean (M), systematic (Σ), and random (σ) differences between the orientation of the prostate and SV were M = −0.4°, Σ = 7.2°, and σ = 6.4°. Daily marker-based corrections required an SV margin of 11.4 mm (translations only) and 11.6 mm (translations + rotations). Rotation corrections of the SVs reduced the required margin to 8.2 mm. Conclusions: We found substantial differences between the orientation of the prostate and SVs. The hybrid registration technique can accurately detect these rotations during treatment. Rotation correction of the SVs allows for margin reduction for the SVs

  14. SU-E-J-20: Adaptive Aperture Morphing for Online Correction for Prostate Cancer Radiotherapy

    International Nuclear Information System (INIS)

    Purpose: Online adaptive aperture morphing is desirable over translational couch shifts to accommodate not only the target position variation but also anatomic changes (rotation, deformation, and relation of target to organ-atrisks). We proposed quick and reliable method for adapting segment aperture leaves for IMRT treatment of prostate. Methods: The proposed method consists of following steps: (1) delineate the contours of prostate, SV, bladder and rectum on kV-CBCT; (2) determine prostate displacement from the rigid body registration of the contoured prostate manifested on the reference CT and the CBCT; (3) adapt the MLC segment apertures obtained from the pre-treatment IMRT planning to accommodate the shifts as well as anatomic changes. The MLC aperture adaptive algorithm involves two steps; first move the whole aperture according to prostate translational/rotational shifts, and secondly fine-tune the aperture shape to maintain the spatial relationship between the planning target contour and the MLC aperture to the daily target contour. Feasibility of this method was evaluated retrospectively on a seven-field IMRT treatment of prostate cancer patient by comparing dose volume histograms of the original plan and the aperture-adjusted plan, with/without additional segments weight optimization (SWO), on two daily treatment CBCTs selected with relative large motion and rotation. Results: For first daily treatment, the prostate rotation was significant (12degree around lateral-axis). With apertureadjusted plan, the D95 to the target was improved 25% and rectum dose (D30, D40) was reduced 20% relative to original plan on daily volumes. For second treatment-fraction, (lateral shift = 6.7mm), after adjustment target D95 improved by 3% and bladder dose (D30, maximum dose) was reduced by 1%. For both cases, extra SWO did not provide significant improvement. Conclusion: The proposed method of adapting segment apertures is promising in treatment position correction

  15. Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.

    Science.gov (United States)

    Foster, Christopher S; Falconer, Alison; Dodson, Andrew R; Norman, Andrew R; Dennis, Nening; Fletcher, Anne; Southgate, Christine; Dowe, Anna; Dearnaley, David; Jhavar, Sameer; Eeles, Rosalind; Feber, Andrew; Cooper, Colin S

    2004-08-01

    E2F transcription factors, including E2F3, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of E2F3-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer. PMID:15184867

  16. Introductory lecture on triple-axis spectrometer

    International Nuclear Information System (INIS)

    Triple-axis spectrometer is a multi-purpose instrument for powder neutron diffraction, single crystal neutron diffraction, powder inelastic neutron scattering, single crystal inelastic neutron scattering, and neutron polarization analysis. In this lecture how to use the triple-axis spectrometer is explained for the beginners. (author)

  17. Vasoactive intestinal peptide signaling axis in human leukemia

    Institute of Scientific and Technical Information of China (English)

    Glenn; Paul; Dorsam; Keith; Benton; Jarrett; Failing; Sandeep; Batra

    2011-01-01

    The vasoactive intestinal peptide (VIP) signaling axis constitutes a master "communication coordinator" between cells of the nervous and immune systems.To date,VIP and its two main receptors expressed in T lymphocytes,vasoactive intestinal peptide receptor (VPAC)1 and VPAC2,mediate critical cellular functions regulating adaptive immunity,including arresting CD4 T cells in G 1 of the cell cycle,protection from apoptosis and a potent chemotactic recruiter of T cells to the mucosa associated lymphoid compartment of the gastrointestinal tissues.Since the discovery of VIP in 1970,followed by the cloning of VPAC1 and VPAC2 in the early 1990s,this signaling axis has been associated with common human cancers,including leukemia.This review highlights the present day knowledge of the VIP ligand and its receptor expression profile in T cell leukemia and cell lines.Also,there will be a discussion describing how the anti-leukemic DNA binding transcription factor,Ikaros,regulates VIP receptor expression in primary human CD4 T lymphocytes and T cell lymphoblastic cell lines (e.g.Hut-78).Lastly,future goals will be mentioned that are expected to uncover the role of how the VIP signaling axis contributes to human leukemogenesis,and to establish whether the VIP receptor signature expressed by leukemic blasts can provide therapeutic and/or diagnostic information.

  18. The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

    International Nuclear Information System (INIS)

    The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes

  19. Cholesterol homeostasis in two commonly used human prostate cancer cell-lines, LNCaP and PC-3.

    Directory of Open Access Journals (Sweden)

    James Robert Krycer

    Full Text Available BACKGROUND: Recently, there has been renewed interest in the link between cholesterol and prostate cancer. It has been previously reported that in vitro, prostate cancer cells lack sterol-mediated feedback regulation of the major transcription factor in cholesterol homeostasis, sterol-regulatory element binding protein 2 (SREBP-2. This could explain the accumulation of cholesterol observed in clinical prostate cancers. Consequently, perturbed feedback regulation to increased sterol levels has become a pervasive concept in the prostate cancer setting. Here, we aimed to explore this in greater depth. METHODOLOGY/PRINCIPAL FINDINGS: After altering the cellular cholesterol status in LNCaP and PC-3 prostate cancer cells, we examined SREBP-2 processing, downstream effects on promoter activity and expression of SREBP-2 target genes, and functional activity (low-density lipoprotein uptake, cholesterol synthesis. In doing so, we observed that LNCaP and PC-3 cells were sensitive to increased sterol levels. In contrast, lowering cholesterol levels via statin treatment generated a greater response in LNCaP cells than PC-3 cells. This highlighted an important difference between these cell-lines: basal SREBP-2 activity appeared to be higher in PC-3 cells, reducing sensitivity to decreased cholesterol levels. CONCLUSION/SIGNIFICANCE: Thus, prostate cancer cells are sensitive to changing sterol levels in vitro, but the extent of this regulation differs between prostate cancer cell-lines. These results shed new light on the regulation of cholesterol metabolism in two commonly used prostate cancer cell-lines, and emphasize the importance of establishing whether or not cholesterol homeostasis is perturbed in prostate cancer in vivo.

  20. Road to Recovery from Prostate Cancer

    Medline Plus

    Full Text Available ... about robotic prostatectomies for the treatment of prostate cancer. During the program, we would like to go ... potency post- surgery. So in 2008, while prostate cancer remains a very controversial subject, it is obviously ...