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)

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.
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PMID:Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. 1255 91

The effects of lovastatin, a potent inhibitor of HMG CoA reductase, on experimental mammary and prostate oncogenesis, were studied in vitro and in vivo. Lovastatin inhibited cell growth in vitro in a dose-dependent manner for both mammary and prostate cancer cell lines, which was associated with p53-independent apoptosis. Flow cytometric analyses of lovastatin-treated mammary and prostate cancer cells demonstrated cell-cycle G(1) arrest, as well as decreases in S and G(2)/M fractions. p21(Waf1) and p27(Kip1) were induced by lovastatin in both types of cancer cells. Gene expression profiling of cells treated with lovastatin, however, was remarkable for a paucity of transcriptional changes induced by lovastatin. Treatment with lovastatin for 4 weeks did inhibit the formation of pre-neoplastic mammary intraepithelial neoplasias (MIN) in vivo, but not invasive carcinomas in the C3(1)/SV40 TAg transgenic model of mammary cancer. The decreased multiplicity of MIN lesions was associated with increased levels of apoptosis in these lesions. However, cell proliferation in the mammary lesions was not significantly different between lovastatin-treated and control mice 1 day after lovastatin treatment. In female mice treated with lovastatin for 12 weeks, there was a tendency for reduced tumor volume, which did not reach statistical significance. However, lovastatin did not suppress any lesion formation in the prostate of C3(1)/SV40 TAg transgenic male mice. Our results suggest that as lovastatin exerts an inhibitory effect on the development of early mammary lesions of mammary carcinogenesis, this compound may be useful for the chemoprevention of mammary cancer and might have utility as an adjuvant in breast cancer therapy. The chemopreventive effects of lovastatin in vivo, however, may be tissue-specific.
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PMID:Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. 1266 4

Cancer chemopreventive effects of inositol hexaphosphate (IP6), a dietary constituent, have been demonstrated against a variety of experimental tumors, however, limited studies have been done against prostate cancer (PCA), and molecular mechanisms are not well defined. In the present study, we investigated the growth inhibitory effect and associated mechanisms of IP6 in advanced human PCA cells. Advanced human prostate carcinoma DU145 cells were used to study the anticancer effect of IP6. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Western immunoblotting, immunoprecipitation and kinase assay were performed to investigate the involvement of G1 cell cycle regulators and their interplay, and end point markers of apoptosis. A significant dose- as well as time-dependent growth inhibition was observed in IP6-treated cells, which was associated with an increase in G1 arrest. IP6 strongly increased the expression of CDKIs (cyclin-dependent kinase inhibitors), Cip1/p21 and Kip1/p27, without any noticeable changes in G1 CDKs and cyclins, except a slight increase in cyclin D2. IP6 inhibited kinase activities associated with CDK2, 4 and 6, and cyclin E and D1. Further studies showed the increased binding of Kip1/p27 and Cip1/p21 with cyclin D1 and E. In down-stream of CDKI-CDK/cyclin cascade, IP6 increased hypophosphorylated levels of Rb-related proteins, pRb/p107 and pRb2/p130, and moderately decreased E2F4 but increased its binding to both pRb/p107 and pRb2/p130. At higher doses and longer treatment times, IP6 caused a marked increase in apoptosis, which was accompanied by increased levels of cleaved PARP and active caspase 3. IP6 modulates CDKI-CDK-cyclin complex, and decreases CDK-cyclin kinase activity, possibly leading to hypophosphorylation of Rb-related proteins and an increased sequestration of E2F4. Higher doses of IP6 could induce apoptosis and that might involve caspases activation. These molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest and apoptotic death of human prostate carcinoma DU145 cells.
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PMID:Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. 1266 18

Androgen-ablation is a most commonly prescribed treatment for metastatic prostate cancer but it is not curative. Development of new strategies for treatment of prostate cancer is limited partly by a lack of full understanding of the mechanism by which androgen regulates prostate cancer cell proliferation. This is due, mainly, to the limitations in currently available experimental models to distinguish androgen/androgen receptor (AR)-induced events specific to proliferation from those that are required for cell viability. We have, therefore, developed an experimental model system in which both androgen-sensitive (LNCaP) and androgen-independent (DU145) prostate cancer cells can be reversibly blocked in G(0)/G(1) phase of cell cycle by isoleucine deprivation without affecting their viability. Pulse-labeling studies with (3)H-thymidine indicated that isoleucine-deprivation caused LNCaP and DU145 cells to arrest at a point in G(1) phase which is 12-15 and 6-8 h, respectively, before the start of S phase and that their progression into S phase was dependent on serum factors. Furthermore, LNCaP, but not DU145, cells required AR activity for progression from G(1) into S phase. Western blot analysis of the cell extracts prepared at regular intervals following release from isoleucine-block revealed remarkable differences in the expression of cyclin E, p21(Cip1), p27(Kip1), and Rb at the protein level between LNCaP and DU145 cells during progression from G(1) into S phase. However, in both cell types Cdk-2 activity associated with cyclin E and cyclin A showed an increase only when the cells transited from G(1) into S phase. These observations were further corroborated by studies using exponentially growing cells that were enriched in specific phases of the cell cycle by centrifugal elutriation. These studies demonstrate usefulness of the isoleucine-deprivation method for synchronization of androgen-sensitive and androgen-independent prostate cancer cells, and for examining the role of androgen and AR in progression of androgen-sensitive prostate cancer cells from G(1) into S phase.
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PMID:Synchronized prostate cancer cells for studying androgen regulated events in cell cycle progression from G1 into S phase. 1270 43

Within the human prostate epithelium four cell populations can be discriminated based on their expression of keratins (K). Basal cells express high levels of K5 and K14, as well as p63, whereas they have very low levels of androgen receptor, prostate-specific antigen (PSA), K8, and K18. Luminal secretory cells lack p63, K5, and K14 but express high levels of K8, K18, androgen receptor, and PSA. Additionally, cells have been identified with a keratin phenotype intermediate between basal and luminal cells that co-express high levels of K5 and K18 (K5/18) as well as hepatocyte growth factor receptor c-MET. Although intermediate cells have been proposed as precursor cells of prostate cancer, their biology is ill defined. Epithelial cells in proliferative inflammatory atrophy (PIA) appear to be cycling rapidly as indicated by expression of Ki-67, and morphological transitions have been identified between PIA and high-grade prostate intraepithelial neoplasia. Many of the atrophic epithelial luminal cells in PIA are candidates for intermediate cells based in part on weak expression of PSA and androgen receptor, high levels of K8/18, and lack of p63. The objective of this study was to further clarify the phenotype of the proposed intermediate cells in PIA and to quantitatively determine the level in which these intermediate cells preferentially occur in PIA lesions. Intermediate cells were immunohistochemically demonstrated using antibodies to K5, K14, K18, and c-MET. Using radical prostatectomy specimens (n = 15) the area fraction of intermediate cells in normally differentiated prostate epithelium and PIA were quantified by a grid point counting method. Atrophic luminal cells of PIA lesions expressed K5 in 39.2 +/- 7.4% of cells compared to 2.4 +/- 2.3% in normal epithelium (P < 0.00001). By contrast, K14 was only expressed in 3.0 +/- 3.2% of the luminal cells. Previous studies have shown that virtually 100% of these atrophic luminal cells are strongly positive for K8/18. c-MET was present in 44.1 +/- 14.1% of luminal cells in PIA but only in 2.1 +/- 2.8% of luminal cells in normal epithelium (P < 0.00001). To unambiguously determine whether intermediate luminal cells in PIA show increased proliferative activity and decreased p27(kip1) expression, double-staining immunofluorescence of Ki-67 and K5, as well as p27(Kip1) and K5 was performed. Luminal cells in PIA often co-expressed K5 and Ki-67. Although p27(Kip1) was strongly expressed in K5-negative differentiated cells in normal epithelium, p27(Kip1) staining was absent in many of the K5-positive cells in the luminal compartment of PIA. We conclude that cells phenotypically intermediate between basal and secretory cells are enriched in PIA lesions. The finding of a large number of highly proliferating intermediate cells in PIA provides further support that these cells may serve as preferred target cells in prostate carcinogenesis.
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PMID:Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy. 1270 36

A multigenic model of prostate cancer susceptibility has been proposed, in which common polymorphic variants of genes, such as the androgen and vitamin D receptor, contribute to tumorigenesis. The discovery of additional genetic factors that contribute to prostate cancer risk should provide opportunities for new approaches to the detection and treatment of this common malignancy. Herein, we examined single nucleotide polymorphic variants in the 3'-untranslated region of CDKN1A (p21(cip1)) and in codon 109 of CDKN1B (p27(kip1)) for association with advanced prostate cancer in a European-American population. Ninety-six cases and 106 controls were analyzed using PCR amplification and restriction digestion assays. CDKN1A genotype was scored as CC, CT, and TT on the basis of the digestion products. The CDKN1A genotypes CT and TT were associated with an increased risk of advanced prostate carcinoma compared with the CC genotype [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.02-4.95]. The CDKN1B genotype was scored as VV, VG, or GG, again on the basis of the digestion products. The CDKN1B genotype VV was also associated with an increased risk of advanced prostate carcinoma (OR, 1.95; 95% CI, 1.09-3.47). These associations were particularly strong in those patients with androgen-independent disease [OR = 2.88 (95% CI, 1.19-6.97) and 2.11 (95% CI, 1.05-4.22) for high-risk genotypes of CDKN1A and CDKN1B, respectively]. In addition, the association of CDKN1B was particularly strong in the cohort of patients under the median age of diagnosis (OR, 2.23; 95% CI, 1.08-4.59). These results suggest that in a European-American population, CDKN1A and CDKN1B variants are associated with advanced prostate cancer. Analysis of CDKN1A and/or CDKN1B genotypes may prove useful in determining which patients are at risk for developing advanced prostate carcinoma and therefore would gain the most from aggressive screening, prophylaxis, and/or treatment.
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PMID:CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. 1272 15

The pathologic grade and clinical stage have some restrictions for the evaluation of the prognosis of prostate carcinoma. Recently, the function of genes related to apoptosis and tumor suppressor genes on the development, progression,and prognostic value of prostate carcinoma was paid close attention due to further research on the molecular pathology of prostate cancer. Overexpression of Bcl-2 was found in high malignant patients of prostate carcinoma and related to androgen refraction and resistance against anticancer agents as well. The mutation of p53 was found in prostatic intraepithelial neoplasia(PIN) and prostate cancer. p53 can be used as an independent prognostic factor for prostate cancer. The deletion of PTEN and p27 is an important negative factor of prognosis. Overexpression of p21 and p16 which are inhibition protein of cell cycle have effects on the formation and differentiation of prostate cancer. Fas/FasL system plays an important role in apoptosis of prostatic epithelial cells and takes part in the carcinogenesis of prostate. BRCA1 and p73 also have effects on the genesis and development of prostate cancer.
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PMID:[Recent advances on molecular pathology of prostate carcinoma]. 1275 24

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. 1286 67

1,25-(OH)2 vitamin D3 (1,25-(OH)2D3) exerts antiproliferative effects via cell cycle regulation in a variety of tumor cells, including prostate. We have previously shown that in the human prostate cancer cell line LN-CaP, 1,25-(OH)2D3 mediates an increase in cyclin-dependent kinase inhibitor p27Kip1 levels, inhibition of cyclin-dependent kinase 2 (Cdk2) activity, hypophosphorylation of retinoblastoma protein, and accumulation of cells in G1. In this study, we investigated the mechanism whereby 1,25-(OH)2D3 increases p27 levels. 1,25-(OH)2D3 had no effect on p27 mRNA levels or on the regulation of a 3.5-kb fragment of the p27 promoter. The rate of p27 protein synthesis was not affected by 1,25-(OH)2D3 as measured by luciferase activity driven by the 5'- and 3'-untranslated regions of p27 that regulate p27 protein synthesis. Pulse-chase analysis of 35S-labeled p27 revealed an increased p27 protein half-life with 1,25-(OH)2D3 treatment. Because Cdk2-mediated phosphorylation of p27 at Thr187 targets p27 for Skp2-mediated degradation, we examined the phosphorylation status of p27 in 1,25-(OH)2D3-treated cells. 1,25-(OH)2D3 decreased levels of Thr187 phosphorylated p27, consistent with inhibition of Thr187 phosphorylation-dependent p27 degradation. In addition, 1,25-(OH)2D3 reduced Skp2 protein levels in LNCaP cells. Cdk2 is activated in the nucleus by Cdk-activating kinase through Thr160 phosphorylation and by cdc25A phosphatase via Thr14 and Tyr15 dephosphorylation. Interestingly, 1,25-(OH)2D3 decreased nuclear Cdk2 levels as assessed by subcellular fractionation and confocal microscopy. Inhibition of Cdk2 by 1,25-(OH)2D3 may thus involve two mechanisms: 1) reduced nuclear Cdk2 available for cyclin binding and activation and 2) impairment of cyclin E-Cdk2-dependent p27 degradation through cytoplasmic mislocalization of Cdk2. These data suggest that Cdk2 mislocalization is central to the antiproliferative effects of 1,25-(OH)2D3.
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PMID:Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. 1295 44

Prostate cancer is among the most common malignancies. It is estimated that 1 in 6 men in the United States will be diagnosed with this disease. Despite the high prevalence and importance of prostate cancer, the molecular mechanisms underlying its development and progression remain poorly understood. This article reviews new information about the roles of oxidants and electrophiles in prostate cancer; the potential importance of chronic inflammation and atrophy in prostate carcinogenesis, and implications for chemoprevention; evidence supporting telomere shortening and genetic instability in the etiology of prostate cancer; and alpha-methylacyl-coenzyme A racemase (AMACR) as a potential marker for prostate carcinogenesis. These new results show that at least some high-grade prostatic intraepithelial neoplasias (PIN) and early adenocarcinomas appear to arise from proliferative inflammatory atrophy (PIA). Inflammation and other environmental factors may lead to the destruction of prostate epithelial cells, and increased proliferation may occur as a response to this cell death. Such proliferation may be mechanistically related to decreased p27(Kip1) observed in PIA. The decreased apoptosis associated with these events may also be related to increased expression of Bcl-2. Increased oxidant and electrophile stress in the setting of increased proliferation associated with these events may lead to elevated glutathione S-transferase P1 (GSTP1) expression as a genomic-protective measure. However, aberrant methylation of the CpG island of the GSTP1 gene promoter silences GSTP1 gene expression and protein levels, setting the stage for additional genetic damage and accelerated progression toward PIN and carcinoma. Additional results show that AMACR may be an important new marker of prostate cancer, and its use in combination with p63 staining may provide the basis for an improved method for identification of prostate cancer.
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PMID:Human prostate cancer precursors and pathobiology. 1460 18


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