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 assessed the ability of cryptophycin 52 (LY355703), a novel antimicrotubule, to induce growth arrest and apoptosis in prostate cancer cell lines and investigated potential molecular mechanisms of death. LNCaP (androgen-dependent) and DU-145 (androgen-independent) cells accumulated in G(2)-M phase of the cell cycle and progressively acquired sub-G(0)-G(1) DNA content after 48 h of exposure to cryptophycin 52 (1-10 pM). Induction of apoptosis was confirmed by DNA ladder formation and detection of cytoplasmic nucleosomes. PC-3 (androgen-independent) cells were less responsive to cryptophycin 52-induced death. Apoptosis was associated with proteolytic processing and activation of the caspase-3-like subfamily proteins caspase-3 and caspase-7 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. The pan-caspase inhibitor BOC-Asp(OMe)-fluoromethylketone effectively reduced cryptophycin 52-induced caspase-3-like protease activity and apoptosis in DU-145 cells. In contrast, BOC-Asp(OMe)-fluoromethylketone did not inhibit apoptosis induction in LNCaP cells by cryptophycin 52, even though both cryptophycin 52-induced caspase-3-like activity and staurosporine-induced death were blocked under identical conditions. Cryptophycin 52 induced phosphorylation of c-raf1 and bcl-2 and/or bcl-x(L) to comparable levels in all cell lines studied, and LNCaP cells overexpressing bcl-2 were more resistant to cryptophycin 52-induced apoptosis. Up-regulation of p53, bax, and p21 expression was induced in wild-type p53-expressing LNCaP cells only after cryptophycin 52 exposure. A sustained increase in c-Jun NH(2)-terminal kinase phosphorylation was also observed, the levels of which strongly correlated with apoptosis. We conclude that apoptosis induced by cryptophycin 52 in prostate cancer cells is androgen status independent, cell type specific for caspase requirement, modulated by the bcl-2 family, linked to but not dependent on p53, and strongly correlated with c-Jun NH(2)-terminal kinase phosphorylation. Cryptophycin 52-induced apoptosis in prostate cancer cells is therefore associated with multiple cell line-specific alterations in apoptosis-associated proteins and pathways.
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PMID:The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells. 1247 8

Phosphorylation of cdk2 on threonine 160 is essential for kinase activity. Mevastatin, an inhibitor of cholesterol synthesis, inhibits cell growth through inhibition of cdk2 and this has been suggested to be due to enhancement of p21 levels. In a prostate cancer cell line, PC3, mevastatin treatment led to elevated levels of p21 and caused a small increase in the p21 associated with cdk2. However, this increase in the associated p21 appeared out of proportion with the resulting dramatic inhibition of kinase activity. Using RNA interference we show that mevastatin inhibits cdk2 activity despite lack of induction of p21, p27, and p57. Instead the kinase was inhibited due to a decrease in activating phosphorylation. Phosphorylation of cdk2 from mevastatin-treated cells with exogenous cyclin-dependent kinase (cdk)-activating enzymes restored its functional activity. The only known mammalian cyclin H.cdk7.mat1 complex (cdk2-activating kinase, Cak), was not inhibited by mevastatin, suggesting either that a different CAK is responsible for cdk2 phosphorylation in vivo or that the regulation is at the level of substrate accessibility or of cdk2 dephosphorylation. These results suggest that mevastatin inhibits cdk2 activity in PC3 cells through the inhibition of Thr-160 phosphorylation of cdk2, providing a novel example of regulation of cdk2 at this level.
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PMID:Inhibition of cdk2 activating phosphorylation by mevastatin. 1247 85

Several studies have identified silibinin as an anticarcinogenic agent. Recently, we showed that silibinin inhibits cell growth via G1 arrest, leading to differentiation of androgen-dependent human prostate carcinoma LNCaP cells (X. Zi and R. Agarwal, Proc. Natl. Acad. Sci. USA, 96: 7490-7495,1999). Here, we extend this study to assess the effect of silibinin on total retinoblastoma protein (Rb) levels and its phosphorylation status, levels of E2F family members, and Rb-E2F binding in LNCaP cells. Compared with controls, silibinin resulted in an increase in total Rb levels that was largely attributable to an increase in unphosphorylated Rb (up to 4.1-fold). This effect of silibinin was mainly attributable to a large decrease (70-97%) in the amount of Rb phosphorylated at specific serine sites. In other studies, silibinin showed a moderate effect on E2F1 but up to 98 and 90% decreases in E2F2 and E2F3 protein levels, respectively. Silibinin treatments also resulted in an increase in the amount of Rb binding to E2F1 (3.8-fold), E2F2 (2.2-fold), and E2F3 (2.2-fold). Cyclin-dependent kinases (CDKs), together with their catalytic subunit cyclins, phosphorylate Rb, which makes transcription factor E2Fs free from Rb-E2F complexes, resulting in cell growth and proliferation. Conversely, CDK inhibitors inhibit this phosphorylation, maintaining E2Fs bound to Rb, which causes growth inhibition. On the basis of our data showing that silibinin induces both unphosphorylated Rb levels and Rb-E2F binding, we also assessed its effect on upstream cell cycle regulators. Silibinin-treated cells showed up to 2.4- and 3.6-fold increases in Cip1/p21 and Kip1/p27 levels, respectively, and a decrease in CDK2 (80%), CDK4 (98%), and cyclin D1 (60%). Consistent with these results, silibinin showed both G1 arrest and growth inhibition. Together, these findings identify modulation of Rb levels and its phosphorylation status as a molecular mechanism of silibinin-induced neuroendocrine differentiation of human prostate carcinoma LNCaP cells and suggest that this could be a novel approach for prostate cancer prevention by silibinin.
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PMID:Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. 1247 70

Genistein (4',5,7-trihydroxyisoflavone) is an isoflavonoid present in soybeans that exhibits anticarcinogenic effects in breast, colon and prostate cancer cells. We recently reported that genistein treatment of the immortalized but nonmalignant human mammary epithelial cell line MCF-10F resulted in growth arrest of MCF-10F cells in the G2 phase of the cell cycle, a large induction of the Tyr15 phosphorylation of Cdc2 (along with decreased activity of Cdc2), increased expression of p21(waf/cip1) and decreased expression of the cell cycle phosphatase Cdc25C. In the present study of MCF-10F cells, genistein rapidly and significantly activated p38, inactivated ERK1/ERK2 and had no effect on SAPK/JNK activity. We also showed that p38 is involved in genistein-induced changes in Cdc2 phosphorylation and that the downregulation of Cdc25C expression by genistein is through the p38 pathway. Finally, we provided evidence that the p38 pathway is involved in genistein-inhibited cell proliferation. These data suggest an important interplay between the p38 pathway and G2 cell cycle checkpoint control and provide insights into possible mechanisms whereby this isoflavone may inhibit early events in mammary carcinogenesis.
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PMID:Genistein activates p38 mitogen-activated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells. 1251 95

Despite the growing interest in selenium intervention of prostate cancer in humans, scanty information is currently available on the molecular mechanism of selenium action. Our past research indicated that methylseleninic acid (MSA) is an excellent reagent for investigating the anticancer effect of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in PC-3 human prostate cancer cells. After exposure to physiological concentrations of MSA, these cells exhibited a dose- and time-dependent inhibition of growth. MSA retarded cell cycle progression at multiple transition points without changing the proportion of cells in different phases of the cell cycle. Flow cytometric analysis of annexin V- and propidium iodide-labeled cells showed a marked induction of apoptosis by MSA. Array analysis with the Affymetrix human genome U95A chip was then applied to profile the gene expression changes that might mediate the effects of selenium. Gene profiling was done in a time course experiment (at 12, 24, 36, and 48 h) using synchronized cells. A large number of potential selenium-responsive genes with diverse biological functions were identified. These genes fell into 12 clusters of distinct kinetics pattern of modulation by MSA. The expression changes of 10 genes known to be critically involved in cell cycle regulation were selected for verification by Western analysis to determine the reliability of the array data. An agreement rate of 70% was obtained based on these confirmation experiments. The array data enabled us to focus on the role of potential key genes (e.g., GADD153, CHK2, p21(WAF1), cyclin A, CDK1, and DHFR) that might be targets of MSA in impeding cell cycle progression. The data also provide valuable insights into novel biological effects of selenium, such as inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling. The present study demonstrates the utility of a genome-wide analysis to elucidate the mechanism of selenium chemoprevention.
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PMID:Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. 1251 77

Prostate cancer (PCa) cells express vitamin D receptors (VDR) and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits the growth of epithelial cells derived from normal, benign prostate hyperplasia, and PCa as well as established PCa cell lines. The growth inhibitory effects of 1,25(OH)(2)D(3) in cell cultures are modulated tissue by the presence and activities of the enzymes 25-hydroxyvitamin D(3) 24-hydroxylase which initiates the inactivation of 1,25(OH)(2)D(3) and 25-hydroxyvitamin D(3) 1alpha-hydroxylase which catalyses its synthesis. In LNCaP human PCa cells 1,25(OH)(2)D(3) exerts antiproliferative activity predominantly by cell cycle arrest through the induction of IGF binding protein-3 (IGFBP-3) expression which in turn increases the levels of the cell cycle inhibitor p21 leading to growth arrest. cDNA microarray analyses of primary prostatic epithelial and PCa cells reveal that 1,25(OH)(2)D(3) regulates many target genes expanding the possible mechanisms of its anticancer activity and raising new potential therapeutic targets. Some of these target genes are involved in growth regulation, protection from oxidative stress, and cell-cell and cell-matrix interactions. A small clinical trial has shown that 1,25(OH)(2)D(3) can slow the rate of prostate specific antigen (PSA) rise in PCa patients demonstrating proof of concept that 1,25(OH)(2)D(3) exhibits therapeutic activity in men with PCa. Further investigation of the role of calcitriol and its analogs for the therapy or chemoprevention of PCa is currently being pursued.
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PMID:Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression. 1252 May 38

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

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10(-5) M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21(Waf1-Cip1), p300/CBP and Apaf-1. The effect of RE on p300/CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR co-activators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time- and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans.
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PMID:Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. 2727 1

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


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