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)

For the typical patient who has newly diagnosed prostate cancer, clinically organ-confined disease of moderate grade, and a PSA less than 10 ng/mL, the current role of imaging studies and molecular biomarkers is limited. Bone scans are not necessary for newly diagnosed men with a PSA less than 10 ng/mL in the absence of bone pain. Similarly, abdominal and pelvic CT scanning rarely provides any useful diagnostic or staging information when the PSA is less the 20 ng/mL and is indicated rarely. Endorectal coil MR imaging adds staging information for patients with a PSA between 10 and 20 ng/mL, a Gleason score of 7 or less, and 50% or more positive biopsies on a sextant sampling. Indium 111 capromab pendetide scanning (ProstaScint) is FDA-approved to evaluate newly diagnosed patients at high risk for metastases. These patients have a Gleason score of 7 or greater and a PSA greater than 20 ng/mL, a Gleason score of 8 to 10 regardless of the PSA value, or clinical stage T3 disease and a Gleason score of 6 or greater. RT-PCR testing of blood or bone marrow for prostate-specific or prostate cancer-specific gene expression, or "molecular staging," is a promising technique whose current use is still investigational. Much useful information may be gained by careful study of prostate needle biopsy material. Aside from current Gleason grading and the number or percentage of cores involved with cancer, no molecular biomarker is approved for clinical use. p27, p53, bcl-2, Ki-67 (MIB-1), and the assessment of neovascularity hold promise, but prospective multicenter studies are needed. In the long-term, multiple gene expression profiling of biopsy material using gene chips may revolutionize the care of patients with prostate cancer and those who elect radical prostatectomy.
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PMID:The role of imaging studies and molecular markers for selecting candidates for radical prostatectomy. 1159 Aug 6

The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G(1) and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling.
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PMID:Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. 1160 46

In the present study, we examined the effects of over-expression of the potential tumor suppressor gene IGFBP-rP1/mac25 on cell-cycle kinetics in prostate cancer cells. The majority of the high expressing IGFBP-rP1/mac25 cell population was located in the G1 and sub-G0/G1 peaks; synchronizing cells in G2/M with nocodazole demonstrated the high expressing IGFBP-rP1/mac25 clones were delayed in the G1 phase of the cell cycle. Unscheduled expression of cyclin A in the sub-G0/G1 peak occurred in the IGFBP-rP1/mac25 clones. Immunoblots showed decreased cyclin D1 and p21 and increased cyclin E, p16, and p27 in the high expressing IGFBP-rP1/mac25 clones compared to the control cells. Cyclin D1/cdk-4,6 and cyclin E/cdk-2 kinase activities decreased but cyclin A/cdk-2 kinase activity increased for the high expressing IGFBP-rP1/mac25 clones compared to control cells. A pRb immunoprecipitation demonstrated more binding of E2F-1 to pRb in the high expressing IGFBP-rP1/mac25 clones than in control cells. Finally, cell senescence, as assessed by senescence-associated beta-galactosidase, demonstrated significantly more staining in the IGFBP-rP1/mac25 cells than control cells. These results suggest that IGFBP-rP1/mac25 alters the cell cycle kinetics of the M12 prostate cell line by delaying the cells in the G1 phase of the cell cycle. In addition, the appearance of cyclin A in the sub-G0/G1 phase of the cell cycle and the increased kinase activity of cyclin A/cdk-2 in the IGFBP-rP1/mac25 clones suggests that cyclin A is associated with the apoptotic cells.
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PMID:Over-expression of insulin-like growth factor binding protein-related protein-1(IGFBP-rP1/mac25) in the M12 prostate cancer cell line alters tumor growth by a delay in G1 and cyclin A associated apoptosis. 1179 Nov 84

1,25-(OH)(2) vitamin D(3) (1,25-(OH)(2) D), the active metabolite of vitamin D, exerts antiproliferative effects on a variety of tumor cells including prostate. This inhibition requires vitamin D receptors (VDRs) as well as downstream effects on the G1 to S phase checkpoint of the cell cycle. Recent data raise the possibility that androgen plays a role in the antiproliferative effects of 1,25-(OH)(2) D in prostate cancer cells; however, this hypothesis has been difficult to test rigorously as the majority of prostate cancer cell lines (unlike human prostate tumors) lack androgen receptors (ARs). We utilized two different models of androgen-independent prostate cancer that express functional ARs and VDRs to evaluate a possible role of androgen in 1,25-(OH)(2) D mediated growth inhibition. We stably introduced the AR cDNA into the human prostate cancer cell line ALVA 31, which expresses functional VDR but is relatively resistant to growth inhibition by 1,25-(OH)(2) D. Neither ALVA-AR nor the control cells, ALVA-NEO, exhibited substantial growth inhibition by 1,25-(OH)(2) D in the presence or absence of androgen. This observation suggests that the basis for the resistance of ALVA 31 to 1,25-(OH)(2) D-mediated growth inhibition is not the lack of AR. The second model was LNCaP-104R1, an AR-expressing androgen independent prostate cancer cell line derived from androgen dependent LNCaP. 1,25-(OH)(2) D inhibited the growth of LNCaP-104R1 cells in the absence of androgen and this effect was not blocked by the antiandrogen Casodex. As was observed in the parental LNCaP cells, this effect was correlated with G1 phase cell cycle accumulation and upregulation of the cyclin dependent kinase inhibitor (CKI) p27, as well as increased association of p27 with cyclin dependent kinase 2. These findings suggest that the antiproliferative effects of 1,25-(OH)(2) D do not require androgen-activated AR but do involve 1,25-(OH)(2) D induction of CKIs required for G1 cell cycle checkpoint control.
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PMID:Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. 1185 Jan 23

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

Prostate cancer (PCA) is the most common histological malignancy and the second leading cause of cancer deaths among North American men. There has been considerable interest in the chemopreventative properties of selenium. In this study, we assessed whether selenium inhibits cell growth and associated cell cycle regulatory proteins. Human PCA cells (LNCaP, PC3, PC3-AR2, and PC3-M) were incubated with and without selenium (Seleno-DL-methionine, 150 microM) for 24, 48, and 72 h. Cells were fixed and stained with propidium iodide for flow cytometry analysis. In parallel experiments, total protein was extracted, immunoprecipitated with cyclin E antibody, and analyzed by Western blot for the expression of cell cycle markers. Treatment with selenium caused G1 arrest and an 80% reduction in the S phase of LNCaP with no effect on PC3. However, PC3 cells transfected with the androgen receptor (PC3-AR2) exhibited a G2/M arrest and a marked reduction (57%) in the S phase during cell cycle progression. In the analysis of cell cycle regulatory molecules, selenium-treated cells demonstrated a significant induction of cyclin-dependent kinase inhibitors Cip1/p21 and Kip1/p27. These data suggest that selenium possesses strong antiproliferative properties in regard to human PCA. This effect appears to be dependent on the presence of a functioning androgen receptor. This provides a theoretical basis for Phase III studies of selenium in PCA prevention.
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PMID:Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines. 1198 Jun 47

In human androgen-independent prostate cancer (PCa), epidermal growth factor receptor (EGFR) regulates angiogenesis, tumor growth, and progression. In this study, we evaluated whether the blockade of EGFR by the anti-EGFR antibody ImClone C225 (IMC-C225) inhibited tumor growth and metastasis by inhibiting angiogenesis, and whether paclitaxel enhanced the results of therapy in androgen-independent PCa. PC-3M-LN4 PCa cells were implanted orthotopically in athymic nude mice and treated with i.p. IMC-C225 (1 mg twice a week) and/or paclitaxel (200 microg once a week). In vitro treatment of PC-3M-LN4 with IMC-C225 inhibited EGFR autophosphorylation without any significant antiproliferative effect. In contrast, in vivo therapy with IMC-C225 alone (P < 0.05) or in combination with paclitaxel (P < 0.005) significantly inhibited PCa growth and metastasis. Serum levels of interleukin (IL) 8 were lower after therapy, and IL-8 mRNA expression was down-regulated within the tumors after therapy. The down-regulation of IL-8 correlated with reduced microvessel density. IMC-C225 reduced tumor cell proliferation, enhanced p27(kip1) expression, and induced tumor and endothelial cell apoptosis. These studies indicate that IMC-C225 has significant antitumor effect in this murine model, mediated in part by inhibition of cellular proliferation and angiogenesis, and by enhancement of apoptosis. The simultaneous administration of paclitaxel enhanced this effect.
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PMID:Inhibition of angiogenesis by the antiepidermal growth factor receptor antibody ImClone C225 in androgen-independent prostate cancer growing orthotopically in nude mice. 1200 46

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27(kip1), the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27(kip1) expression, high (> or = 10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27(kip1), MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27(kip1) was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27(kip1) score is expected if the biopsy p27(kip1) score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27(kip1) assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27(kip1) expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27(kip1) in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.
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PMID:Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer. 1201 37

It has been suggested that the helix-loop-helix protein Id-1 plays an important role in tumourigenesis in certain types of human cancer. Previously, we reported that Id-1 was up-regulated during sex hormone-induced prostate carcinogenesis in a Noble rat model (Ouyang et al. (2001) Carcinogenesis, 22, 965-973). In the present study, we investigated the direct effect of Id-1 expression on human prostate cancer cell proliferation by transfecting an Id-1 expression vector into a prostate cancer cell line LNCaP. Ten stable transfectant clones were isolated and the ectopic Id-1 expression resulted in both increased DNA synthesis rate and the percentage of S phase cells. To study the possible mechanisms involved in the Id-1 induced prostate cancer cell growth, we examined the expression of several factors responsible for G(1) to S phase progression. We found that Id-1 expression induced phosphorylation of RB and down-regulation of p16(INK4a) but not p21(Waf1)or p27(Kip1). Our results indicate that the Id-1 induced inactivation of p16(INK4a)/pRB pathway may be responsible for the increased cell proliferation in prostate cancer cells. Given the fact that both Id-1 over-expression and inactivation of p16(INK4a)/pRB are common events in prostate cancer, our results provide a possible mechanism on the molecular basis of prostate carcinogenesis.
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PMID:Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway. 1201 43

Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-kappaB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.
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PMID:Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. 1203 41


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