UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate growth and differentiation is androgen dependent, and increased expression of matrix metalloproteinase 2 (MMP-2) has been found in more aggressive prostate cancers. As part of our efforts to elucidate the mechanisms responsible for prostate cancer progression, we evaluated the MMP-2 expression after androgen stimulation in human prostate cancer LNCaP and LAPC-4 cells, which express a functional androgen receptor. Treatment of the cells with a synthetic androgen R1881 resulted in an increase of pro-MMP-2 expression assessed by Western blot and gelatinolytic zymography in both cell lines. R1881-stimulated pro-MMP-2 expression occurred in a dose-dependent manner, which was completely abrogated in the presence of the nonsteroid androgen antagonist bicalutamide. In accordance with the protein expression, MMP-2 promoter activity was also increased by R1881 in a cell-based luciferase reporter assay. However, R1881 treatment did not significantly affect either the pro-MMP-9 expression or its promoter activity. Although we observed an appearance of active form of MMP-2, its activator MT1-MMP was not changed after R1881 treatment. Pretreatment of the cells with inhibitors of RNA transcription, actinomycin D, or protein translation, cycloheximide, significantly suppressed R1881-induced pro-MMP-2 expression in LNCaP cells, indicating that androgen stimulates pro-MMP-2 gene expression. In addition, phosphatidylinositol 3'-kinase inhibitor, LY294002 or wortmannin, strongly inhibited R1881-induced pro-MMP-2 expression. Finally, R1881-enhanced LNCaP cell migration was clearly suppressed by LY294002 or the MMP-2 inhibitor OA-Hy in an in vitro migration assay. In conclusion, our data demonstrated that androgen stimulates pro-MMP-2 expression in LNCaP cells via phosphatidylinositol 3'-kinase-dependent androgen receptor transactivation.
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PMID:Androgen stimulates matrix metalloproteinase-2 expression in human prostate cancer. 1269 67

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. The generation of immortalized primary prostate cancer cells that will accurately reflect the in situ characteristics of malignant epithelium is greatly needed. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor. The RC-9 cells transduced through infection with a retrovirus vector expressing the E6 and E7 genes (E6E7) of human papilloma virus-16 (HPV-16) are currently growing well at passage 40, whereas RC-9 cells senesced at passage 7. RC-9/E6E7 cells exhibit epithelial morphology and high level of telomerase activity. More importantly, these immortalized cells produced tumors (SCID5038D) when inoculated into SCID mice. RC-9/E6E7 cells and SCID-5038D cells exhibit a high level of telomerase activity and androgen-responsiveness when treated with R1881. Expression of prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), an androgen-regulated prostate specific gene (NKX3.1), p16, cytokeratins 8, 15 and HPV-16 E6 gene was detected in both of these cells. RC-9/E6E7 and SCID5038D cells also showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1, potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes 2p, 3p, 8p, 13, 14, 16, 17, 18, 21 and the gain of 7 and 20 in the tumor cell line (SCID5038D). These results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate-specific markers and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of a malignant AR and PSA positive established human prostate cancer cell line from a primary tumor of a prostate cancer patient.
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PMID:A novel neoplastic primary tumor-derived human prostate epithelial cell line. 1273 99

Antioxidants, such as vitamin E, are being investigated for efficacy in prostate cancer prevention. In this study, we show that the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), has antiandrogen activity in prostate carcinoma cells. In the presence of PMCol, the androgen-stimulated biphasic growth curve of LNCaP human prostate carcinoma cells was shifted to the right. The PMCol-induced growth shift was similar to that produced by treatment with the pure antiandrogen bicalutamide (i.e., Casodex), indicative of androgen receptor (AR) antagonist activity. The concentration of PMCol used was below the concentration required to affect cell growth or viability in the absence of androgen. Using an AR binding competition assay, PMCol was found to be a potent antiandrogen in both LNCaP and LAPC4 cells, with an IC(50) of approximately 10 micro M against 1 nM R1881 (methyltrienolone; a stable, synthetic androgen). Prostate-specific antigen release from LNCaP cells produced by androgen exposure with either 0.05 or 1.0 nM R1881 was inhibited 100% and 80%, respectively, by 30 micro M PMCol. Also, PMCol inhibited androgen-induced promoter activation in both LNCaP and LAPC4 cells. However, PMCol did not affect AR protein levels, suggesting that the inhibitory effects of PMCol on androgenic pathways were not due to decreased expression of the AR. Therefore, growth modulation by the antioxidant moiety of vitamin E in androgen-sensitive prostate carcinoma cells is due, at least in part, to its potent antiandrogenic activity.
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PMID:Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells. 1293 70

Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.
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PMID:Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. 1297 Jul 46

Mifepristone is a potent antagonist of steroid hormone receptors such as glucocorticoid and progesterone receptors. We investigated the potential for mifepristone to act as an antiandrogen and compared it with partial androgen receptor (AR) agonists and antagonists, in particular bicalutamide. Mifepristone was an effective antiandrogen in vitro that inhibited transcription from three androgen-responsive promoters and blocked the agonist R1881 in a dose-dependent manner. Like bicalutamide, mifepristone also antagonized the action of androgen receptor with a (T877A) mutation. Mifepristone competed effectively with R1881 with a relative binding affinity comparable to that of cyproterone acetate, and much higher than that of hydroxyflutamide and bicalutamide in a binding assay. Mifepristone could effectively induce the binding of the herpes simplex viral protein 16/AR fusion protein to the hormone response elements in the murine mammary tumor virus-luciferase reporter. With either wild-type or T877A mutant AR, mifepristone alone was unable to induce any detectable interaction with coactivators transcriptional intermediary factor-2 or beta-catenin but could inhibit the R1881-induced binding of AR to transcriptional intermediary factor-2 and beta-catenin. Similarly, mifepristone could inhibit the R1881-induced N/C-terminal interaction in a dose-dependent manner even though mifepristone alone has no effect on the N/C-terminal interaction of AR. We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide. The AR-corepressor interaction was also seen in coimmunoprecipitation assays. Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.
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PMID:Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. 1459 76

Tissue inhibitors of metalloproteinases (TIMPs) have been shown to perform several biological functions in tumor promotion, principally by their action of inhibiting matrix metalloproteinases (MMPs) at different steps of the metastatic process. In particular, TIMP-2 is involved in a functional complex with the membrane-type 1 (MT1) MMP to convert the secreted MMP-2 progelatinase into the fully active proteolytic enzyme. We used the human, androgen-sensitive prostate carcinoma cell line LNCaP in coculture with the human osteosarcoma cell line OHS to experimentally address the possibility of androgen-dependent regulatory effects on the functional MT1-MMP/TIMP-2/MMP-2 complex upon interaction between prostate carcinoma and osteoblastic cells in metastasis of prostate cancer to bone. In the LNCaP cells a gradual, time-dependent decline in TIMP-2 mRNA expression was observed in the presence of the synthetic androgen analogue R1881 (100 nM), reaching approximately 25% of the control level after 48 h of incubation. Consistent with this, the accumulation of secreted TIMP-2 in media from R1881-treated cells was significantly inhibited already after 3 h. Neither MMP-2 gelatinolytic activity nor expression of MT1-MMP was detected in LNCaP cells. In contrast, the OHS cells showed membrane-associated MT1-MMP expression as well as MMP-2 secretion. However, R1881 treatment of the LNCaP/OHS coculture model did not seem to change the overall proteolytic activity of the MT1 -MMP/TIMP-2/MMP-2 complex. Hormonal control of TIMP-2 expression in prostate carcinoma cells has not been previously reported, but whether such regulation has any functional role in the development of osteoblastic metastases in prostate cancer is still unclear.
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PMID:The metalloproteinase inhibitor TIMP-2 is down-regulated by androgens in LNCaP prostate carcinoma cells. 1459 88

Zinc levels in the prostate have been reported to be associated with the development and progression of malignant prostate cells. To investigate the reason why the zinc content decreases during the progression of prostate cancer to an androgen-independent state, we compared the expression levels of metallothionein and zinc transporters between androgen-responsive LNCaP cells and its androgen-independent subline, AIDL cells. AIDL cells showed lower zinc levels than LNCaP cells and comparable levels of androgen receptor expression to LNCaP cells, consistent with some clinical aspects of androgen-independent prostatic cancer. AIDL cells exhibited a lower expression of zinc transporter 1 (ZnT1) and higher expression of ZnT3 than LNCaP cells. The content of metallothionein, which is a major zinc-binding protein, was significantly lower in AIDL cells than in LNCaP cells. Furthermore, the expression of ZnT3 mRNA was decreased by incubating LNCaP cells in medium containing hormone-stripped fetal calf serum and increased by addition of synthetic androgen R1881 to the medium, whereas the intracellular zinc levels were not affected under these conditions. These findings suggest that factors such as ZnT1 and metallothioneins other than ZnT3 are associated with the low intracellular zinc content in AIDL cells.
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PMID:Zinc and metallothionein levels and expression of zinc transporters in androgen-independent subline of LNCaP cells. 1466 99

The ability of androgens to inhibit apoptosis in both normal and malignant prostatic cells has been well documented. However, the underlying mechanisms are understood poorly. Here we demonstrated that forkhead transcription factor FKHR (FOXO1)-induced death of LNCaP cells was blocked by a synthetic androgen R1881. Androgen treatment also resulted in a reduction in transcriptional activity of FKHR in these cells. Moreover, treatment of LNCaP cells with R1881 led to a decrease in the intact FKHR protein (70 kDa) and an increase in a faster migrating protein band (60 kDa). Androgen-enhanced appearance of the 60-kDa protein was diminished specifically by lysosomal acidic cysteine protease inhibitors. Mass spectrometry analyses of the purified FLAG-tagged 70- and 60-kDa proteins demonstrated that the 60-kDa species is a FKHR protein product that lacks about 120 amino acid residues of the C-terminal end. Mutagenesis of the basic amino acid Arg(537) in the protease cleavage region, as suggested by mass spectrometry, abrogated both the androgen-induced accumulation of the 60-kDa product and decrease in cell death induced by FKHR, suggesting that the residue Arg(537) is a potential protease cleavage site. Finally, ectopic expression of the first 537 amino acids of FKHR produced an inhibitory effect on transcriptional activity of the intact protein. Together, these results suggest that androgens induce increased activity of an acidic cysteine protease, which in turn cleaves FKHR. This provides a mechanism by which androgens protect prostate cancer cells from the killing effect of FKHR.
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PMID:Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate cancer cells. 1472 21

Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80 microg/ml of GSP), viability (30-80% by 20-80 microg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 microg/ml) resulted in marked inhibition of FCM-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and p38 but had little effect on c-Jun N-terminal kinase under similar experimental conditions. GSP treatment (20-80 microg/ml) to DU145 cells also dose-dependently inhibited FCM-induced activation of NF kappa B concomitantly with inhibition of MMP-2 and -9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in the reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881, resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60 microg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NF kappa B pathways, and thus provides the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
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PMID:Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. 2253 77

Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877-->Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.
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PMID:Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). 1474 61

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