Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mdm2 is a nuclear phosphoprotein which functions as a negative feedback regulator of the p53 tumor suppressor gene. In this study, we investigated the alteration of Mdm2 and p53 in three human cancer cell lines containing either a wild-type or mutant p53 gene after treatment with Adriamycin (doxorubicin, ADR), a DNA damaging agent. We found that human breast cancer MCF-7 cells containing wild-type p53 were much more susceptible to ADR compared to human breast cancer MDA-MB-231 and human prostate cancer Du-145 cells which contain mutant p53. ADR resulted in a significant dose-dependent accumulation of p53 protein in MCF-7 cells, whereas little or no influence was observed on p53 protein of the two mutant p53 cell lines. However, a significant down-regulation of Mdm2 at protein and mRNA levels was observed in these three cell lines following ADR treatment. Moreover, the decrease of Mdm2 was in both a dose- and time-dependent manner. It is interestingly noted that 5 microM is a critical dose for significant down-regulation of the Mdm2 protein. Selected proteasome inhibitors did not rescue the ADR-caused decline in the expression of Mdm2 protein. Therefore, our present results reveal that ADR can induce a down-regulation of Mdm2 via a p53-independent pathway in human cancer cells and the ubiquitin-proteasome degradation mechanism may not be involved in the decreased expression of Mdm2 protein.
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PMID:P53-independent down-regulation of Mdm2 in human cancer cells treated with adriamycin. 1077 10

MDM2 is an oncoprotein that controls tumorigenesis through both p53-dependent and -independent mechanisms. Mdm2 mRNA level is transcriptionally regulated by p53 in response to stress such as DNA damage, and its protein level and subcellular localization are post-translationally modulated by the AKT serine/threonine kinase. Previous studies showed that PTEN, a dual specificity phosphatase that antagonizes phosphatidylinositol 3-kinase/AKT signaling, is capable of blocking MDM2 nuclear translocation and destabilizing the MDM2 protein. Results from our current study demonstrate an additional role for PTEN in regulating MDM2 functions; PTEN modulates Mdm2 transcription and isoform selection by negatively regulating its P1 promoter. In Pten-null cell lines and prostate cancer tissues, Mdm2 P1 promoter activity is up-regulated, resulting in increased L-Mdm2 expression and enhanced p90(MDM2) isoform production. Furthermore, PTEN controls Mdm2 P1 promoter activity through its lipid phosphatase activity, independent of p53. Thus, our results provide a novel mechanism for PTEN in controlling MDM2 oncoprotein functions.
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PMID:PTEN regulates Mdm2 expression through the P1 promoter. 1509 May 41

Although p53-inactivating mutations have been described in the majority of human cancers, their role in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is activated by hypoxia and other stressors and is primarily regulated by the Mdm2 protein. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and other eicosanoids, is also induced by hypoxia. COX-2 and resultant prostaglandins increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2-negative MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was compared in COX-2+ versus COX-2- cells under normoxic and hypoxic conditions. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2-expressing cells exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity, and this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrated a role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and indirect modulation of Mdm2 activity. These data imply that COX-2-positive prostate cancer cells can have impaired p53 function even in the presence of wild-type p53 and that p53 activity can be restored in these cells via inhibition of COX-2 activity.
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PMID:Cyclooxygenase-2 suppresses hypoxia-induced apoptosis via a combination of direct and indirect inhibition of p53 activity in a human prostate cancer cell line. 1555 Apr

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.
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PMID:Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. 1564 Apr 43

Deubiquitinating enzymes can prevent the destruction of protein substrates prior to proteasomal degradation. The ubiquitin-specific protease 2a (USP2a) deubiquitinates the antiapoptotic proteins Fatty Acid Synthase and Mdm2. Here, we show that when USP2a is overexpressed in nontransformed cells, it exhibits oncogenic behavior both in vitro and in vivo and prevents apoptosis induced by chemotherapeutic agents. Notably, USP2a silencing in several human cancer cell lines results in apoptosis. Gene set enrichment analysis, which focuses on groups of genes sharing biological function or regulatory pathways, was done on microarray expression data from human prostate cancers. The cell death-related gene set, as well as a selected cluster of validated p53 target genes, were significantly enriched in the low USP2a expression group of tumors. Conversely, genes implicated in fatty acid metabolism were significantly associated with tumors expressing high USP2a (44%). The expression profile analysis is consistent with the effects of USP2a on its known targets, i.e., Fatty Acid Synthase and Mdm2, defining a subset of prostate tumors resistant to apoptosis. USP2a thus represents a therapeutic target in prostate cancer.
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PMID:The isopeptidase USP2a protects human prostate cancer from apoptosis. 1695 Nov 76

The identification and development of novel nontoxic phytochemicals that target androgen and androgen receptor (AR) signaling remains a priority for prostate cancer (PCA) control. In the present study, we assessed the antiandrogenic efficacy of isosilybin B employing human PCA LNCaP (mutated AR), 22Rv1 (mutated AR) and LAPC4 (wild-type AR) cells. Isosilybin B (10-90 microM) treatment decreased the AR and prostate specific antigen (PSA) levels in LNCaP, 22Rv1 and LAPC4 cells, but not in non-neoplastic human prostate epithelial PWR-1E cells. Isosilybin B treatment also inhibited synthetic androgen R1881-induced nuclear localization of AR, PSA expression and cell growth, and caused G(1) arrest. In mechanistic studies identifying AR degradation, isosilybin B caused increased phosphorylation of Akt (Ser-473 and Thr-308) and Mdm2 (Ser-166), which was linked with AR degradation as pretreatment with PI3K inhibitor (LY294002)-restored AR level. Further, overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation. Antibody pull-down results also indicated that isosilybin B treatment enhances the formation of complex between Akt, Mdm2 and AR, which promotes phosphorylation-dependent AR ubiquitination and its degradation by proteasome. Together, present findings identify a novel mechanism for isosilybin B-mediated anticancer effects in human PCA cells.
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PMID:Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway. 1833 67

The mechanisms by which Ca(2+)-independent phospholipase A(2) (iPLA(2)) mediates cell growth in p53-positive LNCaP and p53-negative PC-3 prostate cancer cell lines were studied. Exposure of cells to the iPLA(2) selective inhibitor bromoenol lactone (BEL; 0-20 microM) induced concentration- and time-dependent decreases in cell growth based on 3-(4, dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide staining and cell number. Decreased cell growth was not caused by cell death as BEL exposure did not alter nuclear morphology or increase annexin V (apoptotic cell marker) or propidium iodide (necrotic cell marker) staining after 48 h. Decreased growth correlated to a G(1)/G(0) arrest in LNCaP cells and aG(2)/M arrest in PC-3 cells. In LNCaP cells, G(1) arrest was preceded by time- (0-48 h) and concentration-dependent (0-10 microM) increases in the expression of the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor p21. Increases in p53 expression preceded increases in p21 expression by 8 h. In LNCaP cells, BEL treatment decreased the expression of the p53 antagonist Mdm2, while increasing Akt phosphorylation. BEL treatment also increased Akt phosphorylation in PC-3 cells, but Mdm2 was not detected. The ability of BEL to increase Akt phosphorylation was inhibited by the phosphoinositide 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]. BEL treatment also decreased agonist-induced activation of the epidermal growth factor receptor. These data suggest that inhibition of iPLA(2) decreases prostate cancer cell growth by p53-dependent and independent mechanisms. Furthermore, alterations in Mdm2 and epidermal growth factor receptor activation following BEL exposure suggest novel roles for iPLA(2) in prostate cancer cell signaling.
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PMID:Inhibition of Ca2+-independent phospholipase A2 decreases prostate cancer cell growth by p53-dependent and independent mechanisms. 1844 Dec 50

Neoplastic transformation of prostate epithelium involves aberrant activation of anti-apoptotic and pro-invasive pathways triggered by multiple poorly understood genetic events. We demonstrated earlier that depletion of mitochondrial DNA (mtDNA) induces prostate cancer progression. Here, using normal prostate epithelial PNT1A cells we demonstrate that mtDNA depletion prevents detachment-induced apoptosis (anoikis) and promotes migratory capabilities onto basement membrane proteins through upregulation of p85 and p110 phosphatidylinositol 3-kinase (PI3K) subunits, which results in Akt2 activation and phosphorylation of downstream substrates GSK3beta, c-Myc, MMP-9, Mdm2, and p53. Pharmacological or genetic PI3K inhibition, siRNA-mediated Akt2 depletion, as well as mtDNA reconstitution were sufficient to restore sensitivity to anoikis and curtail cell migration. Moreover, Akt2 activation induced glucose transporter 1 (GLUT1) expression, glucose uptake, and lactate production, common phenotypic changes seen in neoplastic cells. In keeping with these findings, several prostate carcinoma cell lines displayed reduced mtDNA content and increased PI3K/Akt2 levels when compared to normal PNT1A cells, and Akt2 downregulation prevented their survival, migration and glycolytic metabolism. On a tissue microarray, we also found a statistically significant decrease in mtDNA-encoded cytochrome oxidase I in prostate carcinomas. Taken together, these results provide novel mechanistic evidence supporting the notion that mtDNA mutations may confer survival and migratory advantage to prostate cancer cells through Akt2 signaling.
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PMID:Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2. 1907 38

Androgen receptor (AR) signaling regulates the development and homeostasis of male reproductive organs, including the prostate. Deregulation of AR and AR coregulators, expression, or activity is involved in the initiation of prostate cancer and contributes to the transition of the disease to hormone-refractory stage. The ubiquitous betaArrestin proteins are now recognized as bona fide adapters and signal transducers with target effectors found in both the cytosol and nucleus. Here, we provide evidence that betaArrestin2 forms a complex with AR and acts as an AR corepressor in androgen-dependent prostate cancer cells. Accordingly, the forced overexpression of betaArrestin2 diminishes, and knockdown of betaArrestin2 expression with RNAi increases the androgen-induced prostate-specific antigen (PSA) gene expression. betaArrestin2 serves as an adapter, bringing into close proximity the Mdm2 E3 ligase and AR, thereby promoting AR ubiquitylation and degradation. Human prostate tissues evidence an inverse relationship between the expression of betaArrestin2 and AR activity: glands that express high levels of betaArrestin2 exhibit low expression of PSA, and those glands that express low levels of betaArrestin2 evidence elevated PSA levels. We conclude that betaArrestin2 acts as a corepressor of AR by serving as a scaffold for Mdm2 leading to the AR ubiquitylation and degradation.
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PMID:Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer. 1945 61

We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient rho = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway.
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PMID:Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells. 2057 Aug 99


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