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)

TGF beta can promote and/or suppress prostate tumor growth through multiple and opposing actions. Alterations of its expression, secretion, regulation or of the sensitivity of target cells can lead to a favorable environment for tumor development. To gain a better insight in TGF beta function during cancer progression, we have used different cultured human prostate cells: preneoplastic PNT2 cells, the androgen-dependent LNCaP and the androgen-independent PC3 and DU145 prostate cancer cell lines. We have studied by specific ELISA assays in conditioned media (CM), the secretion of TGF beta 1 and TGF beta 2 in basal conditions and after hormonal treatment (DHT or E2) and the expression of TGF beta 1 mRNA by Northern blot. We have also compared the effect of fibroblast CM on TGF beta secretion by the different cell types. Compared to PNT2 cells, cancer cell lines secrete lower levels of active TGF beta which are not increased in the presence of fibroblast CM. LNCaP cells respond to androgen or estrogen treatment by a 10-fold increase of active TGF beta secretion while PC3 and DU145 are unresponsive. In conclusion, prostate cancer cell lines have lost part of their ability to secrete and activate TGF beta, and to regulate this secretion through stromal-epithelial interactions. Androgen-sensitive cancer cells may compensate this loss by hormonal regulation.
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PMID:Alterations of expression and regulation of transforming growth factor beta in human cancer prostate cell lines. 1258 36

Four human aldo-keto reductases (AKRs) that belong to the AKR1C subfamily function in vitro as 3-keto-, 17-keto- and 20-ketosteroid reductases or as 3alpha-, 17beta- and 20alpha- hydroxysteroid oxidases to varying degrees. By acting as ketosteroid reductases or hydroxysteroid oxidases these AKRs can either convert potent sex hormones (androgens, estrogens and progestins) into their inactive metabolites or they can form potent hormones by catalyzing the reverse reaction. In this manner they may regulate occupancy and trans-activation of steroid hormone receptors. Tissue distribution studies previously indicated that AKR1C2 (type 3 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD)) and AKR1C3 (type 2 3alpha-HSD) are highly expressed in human prostate. An assessment of the directionality of these AKR1C isozymes in a cellular environment would help identify which isozymes are responsible for 5alpha-dihydrotestosterone (5alpha-DHT) formation or its elimination in the prostate. An imbalance in 5alpha-DHT levels has been implicated in development of prostate carcinoma and benign prostatic hyperplasia. We focused our attention on AKR1C2 since this is the isoform that will oxidize 3alpha-androstanediol (3alpha-diol) to 5alpha-DHT in vitro, suggesting it could elevate 5alpha-DHT levels. To determine whether AKR1C2 preferentially functions as a reductase or an oxidase in a cellular context, we transiently transfected AKR1C2 (pcDNA3-AKR1C2) into COS-1 cells and stably transfected pcDNA3-AKR1C2 and pLNCX-AKR1C2 constructs into PC-3 and LNCaP cells, respectively. COS-1 is a monkey kidney cell line, while PC-3 and LNCaP cells are androgen receptor (-) and (+) prostate adenocarcinoma cell lines, respectively. In transient COS-1-AKR1C2 and in stable PC3-AKR1C2 transfectants, AKR1C2 functioned as a 3-ketosteroid reductase inactivating 5alpha-DHT. In androgen dependent human prostate cancer cells LNCaP, it was not possible to ascertain the preferred direction of AKR1C2 by stable transfection due to the high rate of 5alpha-DHT and 3alpha-diol glucuronidation. Based on these findings AKR1C2 may diminish 5alpha-DHT and prevent this ligand from activating the androgen receptor in situ.
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PMID:Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells. 1260 27

Human aldo-keto reductases (AKRs) of the AKR1C subfamily function in vitro as 3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3alpha-, 17beta-, and 20alpha-hydroxysteroid oxidases. These AKRs can convert potent sex hormones (androgens, estrogens, and progestins) into their cognate inactive metabolites or vice versa. By controlling local ligand concentration AKRs may regulate steroid hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in vitro it will catalyze the nicotinamide adenine dinucleotide (NAD(+))-dependent oxidation of 3alpha-androstanediol (3alpha-diol) to 5alpha-dihydrotestosterone (5alpha-DHT). This reaction is potently inhibited by reduced NAD phosphate (NADPH), indicating that the NAD(+): NADPH ratio in cells will determine whether AKR1C2 makes 5alpha-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 transfectants, 5alpha-DHT was reduced by AKR1C2. However, the transfected AKR1C2 oxidase activity was insufficient to surmount the endogenous 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity, which eliminated 3alpha-diol as androsterone. PC-3 cells expressed retinol dehydrogenase/3alpha-HSD and 11-cis-retinol dehydrogenase, but these endogenous enzymes did not oxidize 3alpha-diol to 5alpha-DHT. In stable LNCaP-AKR1C2 transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 transcripts were detected in prostate cancer, but not in cells from normal prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5alpha-DHT and prevents activation of the androgen receptor. AKR1C2 does not act as an oxidase due to either potent product inhibition by NADPH or because it cannot surmount the oxidative 17beta-HSD present. Neither AKR1C2, retinol dehydrogenase/3alpha-HSD nor 11-cis-retinol dehydrogenase is a source of 5alpha-DHT in PC-3 cells.
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PMID:Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells. 1281 May 47

Recent reports suggest that the beta-catenin-T-cell factor (Tcf) (BCT) signaling pathway is important in the progression of prostate cancer. Evidence suggests that the androgen receptor (AR) can repress BCT-mediated transcription both in prostate cancer and colon cancer cells (Chesire and Isaacs, 2002). In this study, we validate such findings and show that repression of BCT signaling is facilitated by competition between the AR and Tcf. Measurements of the Tcf transcriptional reporter (TOPFLASH) indicated that AR+DHT-mediated repression can inhibit BCT transcription in the presence of WT and exogenous activating beta-catenin (Delta1-130 bp). Transient transfections in SW480 cells (APC(mut/mut)) showed that this mode of repression is functionally independent of APC-mediated beta-catenin ubiquitination. Using a recently developed red flourescent protein (HcRed), we demonstrate novel observations about the nuclear distribution of Tcf. Furthermore, with the use of red (HcRed-AR and HcRed-Tcf) and green fusion proteins (beta-catenin-EGFP), we provide morphological evidence of a reciprocal balance of nuclear beta-catenin-EGFP (BC-EGFP). By cotransfecting in LNCaP prostate tumor cells and using quantitative imaging software, we demonstrated a 62.0% colocalization of HcRed-AR and BC-EGFP in the presence of DHT and 63.3% colocalization of HcRed-Tcf/BC-EGFP in the absence of DHT. Costaining for activated RNA Pol II (phosphoserine 2) and HcRed-Tcf suggested that Tcf foci contain transcriptional 'hotspots' validating that these sites have the capacity for transcriptional activity. Given this apparent androgen-dependent competition for nuclear BC-EGFP, we chose to assess our hypothesis by in vivo and in vitro binding assays. SW480 cells transiently transfected with an AR expression construct, treated with DHT and immunoprecipitated for Tcf showed less associated beta-catenin when compared to Tcf precipitates from untreated cells. Furthermore, by treating cells with DHT+Casodex, we were able to abrogate the androgen-sensitive AR/beta-catenin interaction, in addition to relieving transcriptional repression of the TOPFLASH reporter. In vitro binding assays, with increasing amounts of AR(S35), resulted in decreased Tcf(S35) association with immunoprecipitated recombinant beta-catenin-HIS. These data suggest that in steady-state conditions, AR has the ability to compete out Tcf binding for beta-catenin. Finally, using SW480 cells, we show that AR-mediated repression of the BCT pathway has implications for cell cycle progression and in vitro growth. Using FACs analysis, we observed a 26.1% increase in accumulation of cells in the G1 phase of the cell cycle, while in vitro growth assays showed a 35% reduction in viable cells transfected with AR+DHT treatment. Together, our data strongly suggest that a reciprocal balance of nuclear beta-catenin facilitates AR-mediated repression of BCT-driven transcription and cell growth.
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PMID:Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis. 1294 8

Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC). To examine the effects of human androgen receptor (AR) expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145) was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM) resulted in a rapid (maximal at 30 minutes) translocation of AR to the nucleus. Treatment with DHT (5 nM) caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides amodelfor studies ofAR-regulated cell signalling and identification of novel androgen-regulated genes in PC.
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PMID:Ligand activation of the androgen receptor downregulates E-cadherin-mediated cell adhesion and promotes apoptosis of prostatic cancer cells. 1451 6

PC-SPES is an eight-herbal mixture which has activity against prostate cancer cells and can reduce the serum level of prostate specific antigen (PSA) in more than 80% of individuals with prostate cancer. We conducted this study to begin to clarify the molecular mechanism by which PC-SPES inhibited the growth of prostate cancer cells and down-regulated expression of PSA. Western blot analysis, luciferase reporter assay using a variety of promoters of the PSA gene and the isolated androgen receptor response elements (ARE), as well as electrophoretic mobility shift assay (EMSA) were employed to study the effect of PC-SPES on DHT-induced expression of PSA in LNCaP androgen-dependent human prostate cancer cells. Also, Western blot analysis and luciferase reporter assay using 12-0-tetradecanoylphorbol-13-acetate response elements were employed to study the ability of PC-SPES to activate the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 signal pathway in these cells. Reporter studies showed that PC-SPES inhibited DHT-induced PSA promoter/enhancer-luciferase activity via inhibition of ARE transcriptional activity. Western blot analysis showed that PC-SPES down-regulated DHT-induced expression of PSA without decreasing DHT-induced nuclear level of AR. EMSA demonstrated that PC-SPES inhibited the binding of DHT-activated AR to ARE. Moreover, we found that PC-SPES phosphorylated JNK, increased levels of phosphorylated and unphosphorylated forms of c-Jun, and enhanced AP-1 transcriptional activity in LNCaP cells. Interestingly, when LNCaP cells were stably tranfected with the dominant negative JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), these cells no longer underwent apoptosis and growth inhibition in the presence of PC-SPES. But, PC-SPES still decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, PC-SPES inhibited binding of DHT-activated AR to AREs of PSA gene resulting in down-regulation of ARE transcriptional activity and expression of PSA, and this occurred independently of the JNK/c-Jun/AP-1 signal pathway. Also, PC-SPES activated the JNK/c-Jun/AP-1 signal pathway resulting in growth arrest and apoptosis of prostate cancer cells.
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PMID:PC-SPES: Molecular mechanism to induce apoptosis and down-regulate expression of PSA in LNCaP human prostate cancer cells. 1453 91

Members of Shc family conventionally serve as critical adaptors in tyrosine phosphorylation signal transduction pathways. p66(Shc) protein, a member of Shc family, is predominantly expressed in epithelial cells, whereas the regulation of its expression remains an enigma. We describe the effect of steroid hormones on the protein level of p66(Shc) and growth stimulation in hormone-sensitive human prostate, testicular and breast cancer cells. In DHT-treated androgen-sensitive prostate cancer LNCaP C-33 cells, the protein level of p66(Shc) was elevated by approximately 3-fold, correlating with increased cell growth. This DHT effect on p66(Shc) protein level and growth regulation was also observed in another androgen-sensitive prostate cancer cell line MDA PCa2b as well as 2 testicular cancer cell lines, Tera-1 and Tera-2 cells. Similarly, the female sex hormone estrogen had a stimulating effect on p66(Shc) protein level and proliferation in estrogen-sensitive MCF-7 breast cancer cells. The upregulation of p66(Shc) protein level by DHT was competitively abolished by Casodex, an androgen antagonist used to treat prostate cancer. Moreover, immunohistochemical analyses showed that the p66(Shc) protein level was significantly higher in primary prostate tumors than in adjacent non-cancerous cells (p < 0.05). The data collectively indicate that p66(Shc) protein levels correlate with steroid hormone-stimulated cell growth and prostate carcinogenesis.
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PMID:p66Shc protein is upregulated by steroid hormones in hormone-sensitive cancer cells and in primary prostate carcinomas. 1469 93

12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway.
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PMID:JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA). 1513 88

The antiproliferative effect of 1alpha,25(OH)(2)D(3) on human prostate cancer cells is well known, but the mechanism is still not fully understood, especially its androgen-dependent action. Based on cDNA microarray results, we found that long-chain fatty-acid-CoA ligase 3 (FACL3/ACS3) might play an important role in vitamin D(3) and androgen regulation of LNCaP cell growth. The expression of FACL3/ACS3 was found to be significantly upregulated by 1alpha,25(OH)(2)D(3) and the regulation was shown to be time-dependent, with the maximal regulation over 3.5-fold at 96h. FACL3/ACS3 was a dominant isoform of FACL/ACS expressed in LNCaP cells as indicated by measuring the relative expression of each isoform. 1alpha,25(OH)(2)D(3) had no significant effect on the expression of FACL1(FACL2), FACL4 and FACL6 except for its downregulation of FACL5 at 24 and 48h by around twofold. The upregulation of FACL3/ACS3 expression by 1alpha,25(OH)(2)D(3) was accompanied with increased activity of FACL/ACS as demonstrated by enzyme activity assay using a (14)C-labeled substrate preferential for FACL3/ACS3. The growth inhibitory effect of 1alpha,25(OH)(2)D(3) on LNCaP cells was significantly attenuated by FACL3/ACS3 activity inhibitor. Androgen withdrawal (DCC-serum), in the presence of antiandrogen Casodex or in AR-negative prostate cancer cells (PC3 and DU145), vitamin D(3) failed to regulate FACL3/ACS3 expression. The upregulation of FACL3/ACS3 expression by vitamin D(3) was recovered by the addition of DHT in DCC-serum medium. Western blot analysis showed that the expression of androgen receptor (AR) protein was consistent with vitamin D(3) regulation of FACL3/ACS3 expression. Taken together, the data suggest that the upregulation of FACL3/ACS3 expression by vitamin D(3) is through an androgen/AR-mediated pathway and might be one of the contributions of the vitamin D(3) antiproliferative effect in prostate cancer LNCaP cells.
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PMID:The role of long-chain fatty-acid-CoA ligase 3 in vitamin D3 and androgen control of prostate cancer LNCaP cell growth. 1517 14

The growth and development of the prostate gland are regulated by androgens. Despite our understanding of molecular actions of 5alpha-dihydrotestosterone (5alpha-DHT) in the prostate through the trans-activation of the androgen receptor (AR), comprehensive analysis of androgen responsive genes (ARGs) has just been started. Moreover, expression changes induced by the androgen effects of 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), a metabolite of 5alpha-DHT through the action of 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs), remain undefined. We demonstrated that both 5alpha-DHT and 3alpha-diol stimulated similar levels of androgen sensitive human prostate cancer LNCaP cell proliferation. However, consistent with the fact that 3alpha-diol has low affinity toward the AR, 3alpha-diol did not elicit the same levels of AR trans-activation activity as that of 5alpha-DHT. Since LNCaP cells respond to androgen stimulation by transcriptionally activating the AR downstream genes, gene expression patterns between 0 and 48 h following 3alpha-diol and 5alpha-DHT stimulation were analyzed using cDNA-based membrane arrays to define the temporal regulation of ARGs. Array analysis identified 217 and 219 androgen-modulated genes in at least one time point following 3alpha-diol and 5alpha-DHTstimulation, respectively, including key regulators of cell proliferation. Only a subset of these genes (143) was regulated by both androgens. These data suggest that 3alpha-diol exerts androgenic effects independent of the action of 5alpha-DHT in steroid target tissues. Accordingly, 3alpha-diol might activate cell proliferation cascades independent of AR pathway in the prostate.
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PMID:Partitioning of 5alpha-dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol activated pathways for stimulating human prostate cancer LNCaP cell proliferation. 1527 23


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