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)

We have investigated the effect of antioxidant-induced apoptosis in human prostate cancer cell lines that is augmented by testosterone (T). In this study, DU-145 (androgen unresponsive), ALVA-101 (partially androgen responsive), and LNCaP (androgen responsive) were grown in tissue culture with RPMI 1640 medium, 5-10% fetal bovine serum (FBS), antibiotics and 5% CO2. Treatment with 2.5-20 microg/ml of PDTC significantly (P < 0.05, n = 6) lowered cell growth in all three cells 2-60% following treatment for 1-7 days. T (10(-12) M) alone enhances cell growth in androgen responsive cells. In contrast, the combination of PDTC and T significantly (P < 0.05, n = 6) augmented the PDTC induction of apoptosis in the androgen responsive cells, (ALVA-101 and LNCaP), but not in the androgen unresponsive cells (DU-145). PDTC reduced the nuclear NF-KB, as determined with an electrophoretic mobility shift assay (EMSA), to 50% of the control in LNCaP cells, 65% in ALVA-101 cells and 45% in DU-145 cells, but the combination of PDTC and T was not more potent than PDTC alone in any of the cell lines. PDTC suppressed both the AR mRNA and protein expression and reversed the stimulatory effect of T on androgen receptor (AR) protein synthesis in LNCaP and AVLA-101 cells. In conclusion, PDTC is a potent growth inhibitor and an inducer of apoptosis in human prostate cancer cells by reducing nuclear NF-kappaB and AR protein expression. PDTCs suppression of AR synthesis and nuclear NF-kappaB in response to T may contribute to its enhancement of apoptosis observed with T and PDTC compared to PDTC alone.
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PMID:Testosterone is a potential augmentor of antioxidant-induced apoptosis in human prostate cancer cells. 1210 44

Prostate cancer is the second-leading cause of cancer-related deaths in men in the United States. Unfortunately, there is no effective therapy when prostate cancer becomes metastatic and refractory to conventional treatments. For this reason, the identification and exploration of new agents that reduce prostate cancer cell growth are of paramount importance. High consumption of plant-derived phytoestrogens is inversely associated with the incidence and mortality rate of prostate cancer. Previous studies, including our own, have shown that the phytoestrogen genistein inhibits prostate cancer cell growth in vitro and in vivo and decreases secreted and intracellular levels of the androgen-regulated protein prostate-specific antigen (PSA), but the role of genistein as an agonist/antagonist for hormone receptors remains unclear. To elucidate the mechanism by which genistein modulates PSA protein expression in prostate cancer cells, we investigated the effects of genistein on androgen-mediated and estrogen-mediated transcriptional regulation of PSA, androgen receptor (AR) mRNA and protein expression, and the ability of nuclear proteins to bind to androgen-response elements (AREs) in LNCaP cells. We showed that genistein decreased the transcriptional activation of PSA by both androgen-dependent and androgen-independent methods in LNCaP cells. The reduction of androgen-mediated transcriptional activation of PSA was correlated with decreased AR protein and mRNA levels and decreased binding to AREs. In contrast, genistein had differential effects on 17beta-estradiol-mediated PSA expressions. Low concentrations of genistein enhanced 17beta-estradiol-mediated PSA expressions, whereas high concentrations of genistein inhibited estrogen-mediated PSA expression in LNCaP cells. Genistein did not inhibit AR protein expression in the presence of 17beta-estradiol. These results suggest that ligand-dependent differences in the ability to activate PSA expression may contribute to the agonistic/antagonistic responses observed with genistein in prostate cancer cells.
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PMID:Expression of prostate-specific antigen is transcriptionally regulated by genistein in prostate cancer cells. 1211 15

Peptide growth factors have been implicated in progression of prostate cancer (PCa) to the androgen-independent state; however, much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate stroma-derived factor, promotes survival, proliferation, and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro. To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype, we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF (LNCaP/sHB). LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice, in comparison to control cells. LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker, neuron-specific enolase, compared with control tumors. In castrates, increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor (AR) levels. In vitro, AR protein levels were reduced in LNCaP/sHB cells, and in transient transfection assays using an androgen-responsive promoter (mouse mammary tumor virus-long terminal repeat), LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls. This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo. These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence.
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PMID:Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. 1244 87

Androgens are important not only for the development and function of the normal prostate gland, but also for the maintenance of prostate cancer (PCa) cells. The biological function of androgens is exerted by activation of the transcriptional activity of the androgen receptor (AR). The function of the AR in the prostate is largely dependent on AR protein levels and structural integrity of the protein and other transcription activation factors. Based upon the clinical findings that androgen ablation therapy-resistant PCa still expresses AR and the androgen-regulated gene, prostate-specific antigen, a concept is developing that the androgen receptor iscritical for androgen-refractory prostate cancer cells. Indeed, because of the alterations detected in the AR gene, many noncognate activators, including estrogen, progesterone, peptide growth factors, and cytokines, are able to induce transactivation of the AR under androgen-depleted conditions. Also, transactivational activity of the AR is often modulated by crosstalk between the AR and other signaling pathways in cancerous prostatic cells. Dysregulation of AR function in prostate cancer results in an abnormal profile of AR-regulated genes, which include cell cycle regulators, transcription factors, and those proteins important for cell survival, lipogenesis, and secretion. Thus in this review we will evaluate the significance of the AR in the development and progression of prostate cancer.
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PMID:The role of the androgen receptor in prostate cancer. 1244 43

Although many studies have examined the mechanisms of 1,25-dihydroxyvitamin D(3) (calcitriol or 1,25 D) action in different prostate cancer cell lines, little is known regarding the influence of this steroid on the normal prostate. The presence of both VDR and AR in normal prostatic tissues raises the distinct possibility of an important role for this hormone in the normal gland. In order to ascertain the possible role of 1,25 D on both AR and VDR in the normal prostate, the effects of calcitriol and dihydrotestosterone (DHT) on the normal human neonatal prostatic epithelial cell line, 267B-1, were examined. These studies were approached by focusing on how 1,25 D in the presence or absence of DHT affects the distribution of AR and VDR in the cytoplasmic and nuclear compartments of the cells in terms of their protein levels and DNA binding activities. Immunoblot analyses show that 1,25 D increases the AR protein level in both the cytoplasmic and nuclear fractions but not the VDR protein level. On the other hand, the gel shift assays demonstrate that 1,25 D increases both the AR- and VDR-DNA binding activities in the nuclear fraction, whereas there is no increase in DNA binding activities in the cytoplasmic fraction. Addition of DHT along with 1,25 D does not affect the DNA binding activities of both AR and VDR. Overall, these studies suggest that 1,25 D actions on the normal prostate cells may be mediated independently through AR and VDR, respectively.
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PMID:Effects of 1,25-dihydroxyvitamin D3 on the distribution of androgen and vitamin D receptors in human prostate neonatal epithelial cells. 1253 36

Although the progression of prostate cancer initially is dependent on androgens, tumor progression to an androgen-independent growth eventually occurs in most of patients treated with androgen ablation and/or antiandrogen therapy. After the initial response, antiandrogens lose their efficacy and eventually act as agonists to promote androgen receptor (AR)-mediated growth of prostate cancer cells. An aberrant regulation of AR activity, presumably by AR coregulators, may contribute to this acquired agonist activity of antiandrogens. Using an in vitro mutagenesis and a double-negative selection in yeast two-hybrid screening, we have identified a dominant-negative AR coregulator ARA70 (dARA70N), which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells. Whereas ARA70 in oligomeric form interacts with AR and enhances its transcriptional activity, dARA70N lacks AR interaction and might retain the ability to form a non-functional heteromer with ARA70 and interrupt AR transcriptional activity without a change in AR protein itself. The addition of dARA70N reduces the agonist activity and rescues the normal function of antiandrogens in prostate cancer cells. RNA-interference-mediated silencing of ARA70 gene further confirms these observations. Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy. ARA70 may, thus, be a critical target for developing therapeutic agents against AR-mediated progression of prostate cancer.
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PMID:Reducing the agonist activity of antiandrogens by a dominant-negative androgen receptor coregulator ARA70 in prostate cancer cells. 1264 93

Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer. Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.
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PMID:Androgen receptor involvement in the progression of prostate cancer. 1279 Jul 84

The AR (androgen receptor) is a ligand-regulated transcription factor, which belongs to the steroid receptor family and plays an essential role in growth and development of the prostate. Transcriptional activity of steroid receptors is modulated by interaction with co-regulator proteins and yeast two-hybrid analysis is commonly used to identify these steroid receptor-interacting proteins. However, a limitation of conventional two-hybrid systems for detecting AR protein partners has been that they only allow for analysis of the ligand- and DNA-binding domains of the receptor, as its NTD (N-terminal domain) possesses intrinsic transactivation activity. To identify AR N-terminus-interacting proteins, its NTD was used in the RTA (repressed transactivator) system, which is specifically designed for transactivator bait proteins and was shown to be suitable for two-hybrid analysis with the AR NTD. DDC (L-dopa decarboxylase) was detected multiple times as a novel AR-interacting protein, which was subsequently confirmed in vitro and in vivo. Furthermore, transient transfection of DDC in prostate cancer cells strongly enhanced ligand-dependent AR transcriptional activity, an effect that was antagonized using high concentrations of the anti-androgen bicalutamide. Glucocorticoid receptor activity was also strongly enhanced with DDC co-transfection, while oestrogen receptor activity was only mildly affected. Together, our data demonstrate that DDC interacts with AR to enhance steroid receptor transactivation, which may have important implications in prostate cancer progression.
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PMID:Isolation and identification of L-dopa decarboxylase as a protein that binds to and enhances transcriptional activity of the androgen receptor using the repressed transactivator yeast two-hybrid system. 1286 30

Nonsteroidal anti-inflammatory drugs (NSAIDs) play potential roles in cancer chemoprevention. In this study, we investigated the effects of NSAIDs on androgen receptor (AR)-mediated functions in prostate cancer cells. We found that two cyclooxygenase 2-specific NSAIDs, celecoxib and nimesulide, dramatically reduced the expression of androgen-inducible genes, such as prostate-specific antigen, hK2, and the FK506-binding protein 51 (FKBP51). We demonstrated that both NSAIDs repressed AR-mediated activation of prostate-specific antigen and hK2 promoter activity as well as AR protein expression. Finally, our findings suggested that overexpressed c-Jun by the NSAIDs not only inhibited the function of AR but also directly repressed AR expression at the transcription level. Our findings provide a strong rationale for celecoxib and nimesulide as potential agents for prostate cancer prevention and/or treatment.
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PMID:The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells. 1291 9

Vitamin D has been reported to inhibit the growth of prostate cancer cells and model systems. In this study, we examined the interaction between 1,25-dihydroxyvitamin D(3) (1,25 D) in the presence or absence of endogenous testosterone on the growth and development of the adult rat prostate. Male Sprague-Dawley rats (165 days old) were either kept intact or castrated. Seven days after castration, the rats were treated with vehicle (control) or 1,25 D for 3 weeks and then sacrificed. Both ventral and dorsal lateral prostates were harvested; whole tissue lysates were collected and AR and VDR protein levels were analyzed by immunoblot analyses. Administration of 1,25 D in the intact animals decreased the prostatic size by 40%, compared to control animals, whereas 1,25 D did not influence the size of the prostate in castrated rats. 1,25 D administration in intact groups also increased both the AR and VDR protein levels by approximately twofold, whereas in castrated groups, 1,25 D only increased the AR protein level by 1.5-2.5-fold. 1,25 D in the presence of endogenous testosterone inhibits prostatic growth, whereas 1,25 D in the absence of endogenous testosterone does not affect prostatic growth. The growth inhibitory activity of 1,25 D in the presence of testosterone may be mediated through the ligand activated AR and VDR pathways. These studies may reveal important information about the potential efficacy of 1,25 D as well as hormonal status in understanding the development of prostate diseases.
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PMID:Vitamin D and androgen regulation of prostatic growth. 1293 63


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