Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The link between ERG rearrangement and PTEN (phosphatase and tensin homolog deleted on chromosome 10) deletion is unclear in prostate cancer progression. Using fluorescence in situ hybridization, we systematically validated the frequency and distribution of ERG and PTEN aberrations in a cohort of 73 benign prostate tissues, 59 high-grade prostatic intraepithelial neoplasia (HGPIN) foci, 281 localized prostate cancer and 47 androgen-independent metastatic prostate cancer patients. Overall, ERG rearrangement was present in 15% (5/33) of HGPIN, 45% (121/267) of localized cancers and 35% (15/43) of metastases. By contrast, PTEN deletion was identified in 9% (3/33) of HGPIN, 17% (42/251) of localized cancers and 54% (22/41) of metastases, of which 0%, 40% (17/42) and 45% (10/22) were homozygous, respectively. Concomitance of ERG rearrangement and PTEN deletion was observed in a subset of HGPIN. Significantly, association between PTEN deletion and ERG rearrangement was present both in localized cancers (P=0.0008) and metastases (P=0.02). Further, immunohistochemistry revealed significant correlation of decreased PTEN protein expression with PTEN genomic deletion both in localized and metastatic cancer. Of note, ERG aberration, but not PTEN deletion, was consistently identical both in localized cancer and adjacent HGPIN. Similarly, whereas all metastases (41/41, 100%) shared the same ERG status across multiple sites from the same patient, 5% (2/41) of cases showed discordance for PTEN deletion status across multiple sites. Collectively, our data support PTEN deletion as a late genetic event in human prostate cancer, presumably a 'second hit' after ERG rearrangement. PTEN deletion and ERG rearrangement may cooperate, but contribute at different stages, in prostate cancer progression.
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PMID:Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. 1940 51

Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-kappaB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-kappaB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-kappaB pathway as a critical event in prostate tumorigenesis.
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PMID:Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma. 1947 Apr 63

Although the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is frequently mutated or deleted in a wide variety of solid tumors, some malignancies, including prostate cancer, exhibit undetectable PTEN protein without loss of PTEN gene. Aim of this study was to evaluate whether the PTEN downmodulation, observed during bicalutamide treatment, was due to epigentic events. We analyzed the expression of PTEN in presence or absence of azacitidine or valproic acid in a panel of 50 primary cultures derived from naive (UNT, 23 ptz) and bicalutamide-based neoadjuvant hormone therapy-treated patients (NHT, 27 pts). Results showed that Western blot and PCR analyses showed that 54 and 68% of primary cultures displayed detectable amounts of PTEN protein and mRNA, respectively. Treatment with azacitidine increased the percentage of PTEN-positive cultures up to 72 and 80% for PTEN protein and mRNA determination, respectively. Treatment with valproic acid was able to increase the percentage of PTEN-positive cultures up to 80 and 74% for PTEN protein and mRNA determination, respectively. The percentage of cultures with undetectable levels of PTEN protein was significatively higher in cultures derived NHT patients respect to cultures derived from UNT men (P=0.020). Valproic acid reduced significantly the percentage of cultures PTEN-negative only at protein level and only in NHT (P=0.029) group. In conclusion, our data suggests that antiandrogenic therapy reduced PTEN expression by epigenetic mechanisms suggesting that epigenetic drugs, upmodulating PTEN expression, can reduce Akt activity and probably enhance the efficacy of antiandrogenic therapy.
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PMID:Epigenetic modulation of PTEN expression during antiandrogenic therapies in human prostate cancer. 1978 68

Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss-induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro-senescence" approach for cancer prevention and therapy.
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PMID:A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. 2046 84

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol 3-kinase-Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b~25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b~25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a proto-oncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.
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PMID:Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. 2038 16

Epidemiological evidence suggests a lower incidence of prostate cancer in Asian countries, where soy products are more frequently consumed than in Western countries, indicating that isoflavones from soy have chemopreventive activities in prostate cells. Here, we tested the effects of the soy isoflavone genistein on antioxidant enzymes in DU145 prostate cancer cells. Genistein significantly decreased reactive oxygen species levels and induced the expression of the antioxidant enzymes manganese (Mn) superoxide dismutase (SOD) and catalase, which were associated with AMP-activated protein kinase (AMPK) and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathways. The induced expression of catalase, MnSOD, and PTEN were attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating the effects of genistein primarily depend on AMPK. Furthermore, PTEN is essential for genistein activity, as shown by PTEN transfection in PTEN-deficient PC3 cells. Thus, genistein induces antioxidant enzymes through AMPK activation and increased PTEN expression.
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PMID:The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. 2067 57

The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) and the androgen receptor (AR) play important roles in tumor development and progression in prostate carcinogenesis. Among many functions, PTEN negatively regulates the cytoplasmic phosphatidylinositol-3-kinase/AKT anti-apoptotic pathway; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via cyclin D. Decreased PTEN expression is correlated with prostate cancer progression. Over-expression of AR and upregulation of AR transcriptional activity are often observed in the later stages of prostate cancer. Recent studies indicate that PTEN regulates AR activity and stability. However, the mechanism of how AR regulates PTEN has never been studied. Furthermore, resveratrol, a phytoalexin enriched in red grapes, strawberries and peanuts, has been shown to inhibit AR transcriptional activity in prostate cancer cells. In this study, we use prostate cancer cell lines to test the hypothesis that resveratrol inhibits cellular proliferation in both AR-dependent and -independent mechanisms. We show that resveratrol inhibits AR transcriptional activity in both androgen-dependent and -independent prostate cancer cells. Additionally, resveratrol stimulates PTEN expression through AR inhibition. In contrast, resveratrol directly binds epidermal growth factor receptor (EGFR) rapidly inhibiting EGFR phosphorylation, resulting in decreased AKT phosphorylation, in an AR-independent manner. Thus, resveratrol may act as potential adjunctive treatment for late-stage hormone refractory prostate cancer. More importantly, for the first time, our study demonstrates the mechanism by which AR regulates PTEN expression at the transcription level, indicating the direct link between a nuclear receptor and the PI3K/AKT pathway.
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PMID:Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. 2072 95

Prostate cancer (PCa) is the most common non-skin cancer diagnosed in North America, and it affects 1 in 6 men. Patients with recurrent or metastatic pca will inevitably develop castration-resistant disease after an initial period of hormone responsiveness. The standard first-line treatment for men with castration-resistant pca (CRPC) is docetaxel, but further treatment options are limited. This review summarizes the research being conducted in CRPC, with specific regard to immunotherapy and to novel targeted therapies directed against the androgen axis, vascular endothelial growth factor, chaperone proteins, the phosphoinositide 3 kinase/Akt/phosphatase and tensin homolog/mammalian target of rapamycin pathway, and endothelin-1.
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PMID:Research in castration-resistant prostate cancer: what does the future hold? 2088 38

A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.
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PMID:Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer. 2130 Aug 90

Inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is heavily implicated in the tumorigenesis of prostate cancer. Conversely, the upregulation of the chemokine (CXC) receptor 4 (CXCR4) is associated with prostate cancer progression and metastasis. Studies have shown that loss of PTEN permits CXCR4-mediated functions in prostate cancer cells. Loss of PTEN function is typically due to genetic and epigenetic modulations, as well as active site oxidation by reactive oxygen species (ROS); likewise ROS upregulates CXCR4 expression. Herein, we show that ROS accumulation permitted CXCR4-mediated functions through PTEN catalytic inactivation. ROS increased p-AKT and CXCR4 expression, which were abrogated by a ROS scavenger in prostate cancer cells. ROS mediated PTEN inactivation but did not affect expression, yet enhanced cell migration and invasion in a CXCR4-dependent manner. Collectively, our studies add to the body of knowledge on the regulatory role of PTEN in CXCR4-mediated cancer progression, and hopefully, will contribute to the development of therapies that target the tumor microenvironment, which have great potential for the better management of a metastatic disease.
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PMID:ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. 2162 59


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