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 incidence of prostate cancer varies greatly throughout the world; it is highest in African-Americans and lowest in the Asian populations of China, India, and Japan. Geographical differences in both prevalence of latent prostate cancer and mortality have been postulated to be influenced by diverse tumor-promoting and protective factors, both environmental and dietary. Prostate cancer is a tumor with an extremely long latency; the pattern of prostate tumorigenesis, in terms of the display and sequence of appearance of particular molecular or biochemical features, or morphological changes, characterizing different stages of the carcinogenic process, is expected to be heterogeneous. Some insights into tumor heterogeneity and progression can be obtained from studies using cell lines, particularly those derived from different anatomical sites. The present study aims to investigate whether hormone-responsive LNCaP and androgen-refractory JCA-1, PC-3, and DU-145 prostate cancer cells are responsive to Yunzhi (YZ), a proprietary dietary supplement prepared from extracts of Trametes versicolor, also known as Coriolus versicolor (a mushroom consumed by Chinese for its purported health benefits), and to elucidate its mechanism of action. Ethanolic extracts (70%) of YZ significantly reduced LNCaP cell growth, down-regulated the levels of secreted PSA, but had less effects on the expression of intracellular PSA and did not affect levels of the androgen receptor. In androgen-unresponsive prostate cancer cells, YZ had a much less pronounced suppressive effect on proliferation of PC-3 and DU-145 cells, compared to LNCaP, and was inactive against JCA-1 cells. Western blot analyses show that the expression of Rb, a key regulatory protein in G1/S transition, and PCNA, integrally involved in mammalian cell DNA replication, were significantly reduced by treatment with YZ in PC-3 and DU-145 cells, respectively. In contradiction, none of these biochemical parameters were affected in JCA-1 cells under identical treatment conditions. Further analysis shows that YZ increased the levels of signal transducer and activator family of transcription factors STAT 1 and STAT 3 in JCA-1 and not LNCaP cells. The greater sensitivity of LNCaP cells to this polysaccharopeptide raises the possibility that YZ may be considered as an adjuvant therapy in the treatment of hormone responsive prostate cancer; additionally, it may have chemopreventive potential to restrict prostate tumorigenic progression from the hormone-dependent to the hormone-refractory state.
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PMID:Cell growth and gene modulatory activities of Yunzhi (Windsor Wunxi) from mushroom Trametes versicolor in androgen-dependent and androgen-insensitive human prostate cancer cells. 1111 42

Diagnostic and prognostic markers for prostatic cancer (PCa) include conventional protein markers (e.g., PAP, PSA, PSMA, PIP, OA-519, Ki-67, PCNA, TF, collagenase, and TIMP 1), angiogenesis indicator (e.g., factor VIII), neuroendocrine differentiation status, adhesion molecules (E-cadherin, integrin), bone matrix degrading products (e.g., ICPT), as well as molecular markers (e.g., PSA, PSMA, p53, 12-LOX, and MSI). Currently, only PSA is used clinically for early diagnosis and monitoring of PCa. The histological differential diagnosis of prostatic adenocarcinoma includes normal tissues such as Cowper's gland, paraganglion tissue and seminal vesicle or ejaculatory duct as well as pathological conditions such as atypical adenomatous hyperplasia, atrophy, basal cell hyperplasia and sclerosing adenosis. A common PCa is characterized by a remarkable heterogeneity in terms of its differentiation, microscopic growth patterns and biological aggressiveness. Most PCa are multifocal with signi ficant variations in tumor grade between anatomically separated tumor foci. The Gleason grading system which recognizes five major grades defined by patterns of neoplastic growth has gained almost uniform acceptance. In predicting the biologic behavior of PCa clinical and pathological stages are used as the major prognostic indicators. Among the cell proliferation and death regulators androgens are critical survival factors for normal prostate epithelial cells as well as for the androgen-dependent human prostatic cancer cells. The androgen ablation has been shown to increase the apoptotic index in prostatic cancer patients and castration also promotes apoptotic death of human prostate carcinoma grown in mice. The progression of PCa, similarly to other malignancies, is a multistep process, accompanied by genetic and epigenetic changes, involving phenomenons as adhesion, invasion and angiogenesis (without prostate specific features).
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PMID:Prostate Cancer - Old Problems and New Approaches. (Part II. Diagnostic and Prognostic Markers, Pathology and Biological Aspects). 1117 6

Functional overexpression of Bcl-2 has been reported to confer an anti-apoptotic potential in a variety of cell types. The role of Bcl-2 in epithelial cell-cycle control and in interactions with other cell-cycle regulators is not clearly understood. Its expression has been correlated with the hormono- and chemo-resistant phenotype in advanced prostate cancer. The aim of this study was to investigate the mechanisms through which Bcl-2 mediates increased cytotoxic chemoresistance by assessing alterations in the expression of cell death regulatory molecules. The DU145 human prostatic adenocarcinoma cell line was stably transfected with a Bcl-2 encoding expression plasmid. Two Bcl-2 transfectants, DKC9 and DKC11, were expanded for further study. The effects of Bcl-2 expression on cellular proliferation, cell death (+/- adriamycin or thapsigargin), and expression of cell-cycle/death regulators (p53, PCNA, Bax, Bak, Bcl-X(L)) were evaluated. Compared with controls, Bcl-2 transfectants showed no difference in the rate of proliferation, a decrease in p53 (approximately two-fold), an increase in Bax (approximately two-fold) and PCNA (approximately three-fold), and no change in the levels of Bcl-X(L) and Bak proteins. DKC9 and DKC11 also exhibited a significantly increased chemoresistance to adriamycin (0.0025-5 microM) and thapsigargin (0.0025-5 microM) compared with controls. In the presence of thapsigargin or adriamycin, levels of Bcl-2 and its heterodimeric partner Bax were elevated approximately two-fold with no change in Bak in Bcl-2 transfectants in contrast to controls, where Bak was increased (two-fold). This is the first study to demonstrate that Bcl-2 transfection modulates the expression of mutant p53, Bax, and PCNA in prostate cancer cells. Moreover, Bcl-2 overexpression conferred a significant cytotoxic chemoresistance and altered the balance of expression of death promoters (from Bak, a dominant death promoter in controls, to Bax) in response to thapsigargin and adriamycin.
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PMID:Differential expression of cell death regulators in response to thapsigargin and adriamycin in Bcl-2 transfected DU145 prostatic cancer cells. 1127 13

Locally secreted growth factors and neuropeptides may play an important role in sustaining the growth of hormone-independent prostate cancer. Our previous studies have shown that calcitonin-like immunoreactive peptide (CTI) is secreted by primary prostate cells in culture, and its secretion from malignant prostate cells is significantly higher than benign cells. Exogenously added calcitonin (CT) induces DNA synthesis in serum-starved prostate cancer LNCaP and PC-3M cells. Present studies extended these findings by cloning cDNAs for CT and CT receptor (CT-R) from prostate cancer cells and studying the expression of CT and CT-R mRNA in prostate cancer cell lines and primary prostate tumor specimens. The results have shown that PC-3 cells expressed CT, and not CT-R, mRNA, whereas CT-R, but not CT, mRNA was expressed by LNCaP cells. Conditioned media from PC-3 cells induced DNA synthesis of LNCaP cells, and this mitogenic response was abolished by anti-CT serum. Highly aggressive PC-3M cells co-expressed CT and CT-R mRNAs. CT also induced a twofold increase in DNA synthesis of primary prostate cells and anti-CT serum caused a 56% decline. In-situ hybridization histochemistry of archival prostate specimens has selectively localized CT and CT-R mRNA in basal epithelium of benign and low grade PC specimens, and these mRNAs were not detected in either luminal epithelium or stroma. In contrast, CT and CT-R mRNA were detected throughout the luminal epithelium of moderate and high-grade PC specimens. Most epithelial cells of low and moderately differentiated tumors expressed either CT or CT-R mRNA, suggesting that CT may serve as a paracrine factor. In contrast, CT and CT-R mRNAs were co-expressed by most tumor cells in advanced PC specimens. The cells expressing CT-R mRNA in primary tumors also co-expressed PCNA. These results, when combined with mitogenic actions of CT on primary prostate cells as well as PC cell lines, strongly support the role for CT in sustaining the growth of cancer cells.
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PMID:Calcitonin is a prostate epithelium-derived growth stimulatory peptide. 1147 42

PC SPES (BotanicLab, Brea, California) an herbal supplement for patients with prostate cancer, is composed of 7 highly concentrated Chinese herbs and 1 US herb. It was developed in seeking positive attributes of Chinese and Western medicine for cancer treatment. Chemical standardization of this composition showed that baicalin is the most abundant active compound. Several reports on phase 2 clinical studies of PC SPES suggest that it is a well-tolerated active treatment for androgen-independent prostate cancer. In this report, data obtained from various laboratory experiments will be presented to elucidate the in vitro mechanism. Profound biologic effects of PC SPES on prostate cancer cells were observed on both androgen-dependent (LNCap) and androgen-independent (DU-145) cell lines. These effects include the following: (1) induction of cell apoptosis and cell cycle modulation; (2) inhibition of cell proliferation; (3) downregulation of bcl-2, bcl-6, proliferating cell nuclear antigen, and prostate-specific antigen proteins; (4) downregulation of androgen receptor (AR); and (5) upregulation of p53, bax, and p21 proteins. Concurrent animal studies using 2 different models, Copenhagen rats and nude mice, confirmed a dose-dependent suppressive effect of PC SPES on tumor volumes and tumor progression. Our results show that the cytotoxic and cytostatic properties of PC SPES are not entirely dependent on the presence of AR. The antitumor mechanism of PC SPES is complex. It involves multiple metabolic pathways, such that the whole extract acts on redundant mechanisms, which otherwise will permit cell survival if a single-target agent is used.
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PMID:In vitro mechanism of PC SPES. 1150 43

Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.
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PMID:Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. 1150 10

The effects of the 17beta-estradiol, dihydrotestosterone and hormone antagonists tamoxifen and bicalutamide on telomerase activity and expression of cell cycle related proteins in the androgen-sensitive prostatic cancer cell line LNCaP were studied. The cell line was grown in RPMI supplemented with 2.5% charcoal-stripped FBS for 72 hr. The IC(50) of tamoxifen and bicalutamide and the optimal stimulatory concentrations of 17beta-estradiol and dihydrotestosterone were determined by means of the cell-viability assay, the activity of telomerase was measured by the telomere repeat amplification protocol (TRAP) and the expression of proteins was analysed by the Western blot technique. 17beta-estradiol stimulated cell growth more effectively than dihydrotestosterone whereas hormone antagonists tamoxifen and bicalutamide caused a significant decrease in cell viability. The treatment of cells by a combination of low doses of 17 beta-estradiol and dihydrotestosterone stimulated cells stronger than treatment by a single hormone. Only 17beta-estradiol, in concentration of 10nM, increased strongly the expression of p21(Waf1/Cip1) and increased slightly telomerase activity in the LNCaP cells. 50 microM of bicalutamide down-regulated the levels of the androgen receptor, the proliferating cell nuclear antigen and telomerase activity, and up-regulated the expression of p27(Kip1). We hereby describe the first observation of the influence of bicalutamide on telomerase activity and a positive correlation between the effect of 17beta-estradiol and the induction of both the endogenous cyclin-dependent kinase inhibitor, p21(Waf1/Cip1), and telomerase activity in a prostatic cancer cell line LNCaP. These findings can shed a new light on the steroid-signaling pathway in prostate cancer cells.
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PMID:The effects of natural ligands of hormone receptors and their antagonists on telomerase activity in the androgen sensitive prostatic cancer cell line LNCaP. 1193 51

Previous studies have suggested that the clinical efficacy of PC-SPES, a dietary supplement used frequently by men diagnosed with androgen-dependent (AD) or androgen-independent (AI) prostate cancer (CaP), is mechanistically attributed to estrogenic components present in the herbal mixture. To test this hypothesis, we compared estradiol (1 nM), potentially an active principle in PC-SPES, with PC-SPES (using an amount equivalent to 1 nM estradiol) on cell proliferation, induction of apoptosis, and regulation of prostate specific genes, PSA and AR, in androgen-responsive LNCaP cells. Cells cultured in steroid-proficient (FBS) or-deficient (CS-FBS) media to simulate hormonal status pre- and post-castration in vivo, were incubated with estradiol or PC-SPES. Proliferation was reduced in PC-SPES treated cells cultured in media supplemented with FBS or CS-FBS; in contrast, addition of estradiol had no effect on proliferation in FBS cultures, and elicited a 45% growth increase in CS-PBS-supplemented cultures. The differential proliferative response of LNCaP cells to PC-SPES vs. estradiol was also supported by changes in PCNA expression, cell viability, cell cycle phase distribution, and induction of apoptosis. Estradiol elicited time-dependent increases in secreted PSA, whereas PC-SPES suppressed PSA secretion, in both culture conditions. In FBS cultures, PC-SPES lowered intracellular AR and PSA by 61% and 17%, respectively, while estradiol increased intracellular PSA, in parallel with a 42% decrease in AR expression. In comparison with cells maintained with CS-FBS, estradiol induced substantial increases in both intracellular PSA and AR, whereas PC-SPES resulted in a smaller increase in intracellular PSA without affecting the expression of AR. These studies show that the antiproliferative and gene modulatory effects of PC-SPES in androgen-dependent human prostate cancer cells are mechanistically and functionally distinct from effects attributable to estradiol.
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PMID:Effects of PC-SPES on proliferation and expression of AR/PSA in androgen-responsive LNCaP cells are independent of estradiol. 1217 83

Prostate carcinoma (PCa) is the most common male cancer in industrialized societies and represents a serious public health problem. The aim of our study was the immunohistochemical evaluation of Ki-67 and proliferating cell nuclear antigen (PCNA) expression in prostate cancer (PCa) following radical prostatectomy and analysis of its relationship to chosen anatomo-clinical and morfological parameters of the tumours. Archival sections from 28 PCas were immunostained with monoclonal antibodies against Ki-67, and proliferating cell nuclear antigen (PCNA). Immunolocalization of Ki-67 and PCNA was performed using LSAB method. No statistically significant correlation was found between the expression of Ki-67, PCNA and preoperative PSA level, lymph node metastases, capsular penetration, seminal vesicle invasive and positive or negative surgical resection margins. However, a strong statistically significant correlation between Ki-67 positive and T stage was found. We also found relationship between Gleason score 7 or above and high expression of Ki-67 and PCNA in prostate cancers (p < 0.004, p < 0.02 respectively). These results suggest that PCNA and especially Ki-67 may be useful as tumour markers in prostate carcinoma, but further studies on larger group are required.
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PMID:Expression of Ki-67 and PCNA as proliferating markers in prostate cancer. 1253 69

PC-SPES is an herbal mixture, with evidence of clinical efficacy against prostate cancer (CaP), recently attracting tremendous attention. Using immunoblot and cell cycle specific cDNA array analyses, we investigated effects of PC-SPES on LNCaP, a hormone-dependent prostate cancer cell line. PC-SPES inhibited expression of cyclins D and E, inhibited Rb phosphorylation, switching it to a G1-to-S inhibitory state. Moreover, cDNA array analysis showed that PC-SPES caused up-regulation of p21(WAF1/CIP1) and decreased expression of cyclin B, Nedd8, cdc2, skp1, PCNA, MAD2L1, cyclin H, CKS2, E2F, Rbx1, MCM2, MCM5, Mpp2, Cullin-Cul4A, Cks1p9 and McM7, which are involved in cell cycle progression. Taken together, our results provide a mechanistic explanation for antiproliferative and antitumor effects of PC-SPES, suggesting that induction of CDK inhibitors and downregulation of cyclins leads to dephosphorylation of Rb and growth arrest.
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PMID:PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cycle-related genes in prostate cancer cells. 1269 90


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