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)

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

Selenium has been implicated as a promising chemopreventive agent for prostate cancer. Whereas the anticancer mechanisms have not been clearly defined, one hypothesis relates to selenium metabolites, especially the monomethyl selenium pool, generated under supranutritional selenium supplementation. To explore potential molecular targets for mediating the chemopreventive activity, we contrasted the effects of methylseleninic acid (MSeA), a novel precursor of methylselenol, versus sodium selenite, a representative of the hydrogen selenide metabolite pool, on apoptosis execution, cell cycle distribution, and selected protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to 3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater concentrations led to not only G1 arrest, but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by the subapoptogenic doses of MSeA was associated with increased expression of p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of phosphorylation of protein kinase AKT and extracellular signal-regulated kinase (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast, selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA fragmentation, which were associated with decreased expression of p27kip1 and p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase added into the cell culture medium, cell detachment and DNA nucleosomal fragmentation induced by selenite exposure were greatly attenuated by this enzyme, supporting a chemical mediator role of superoxide for these processes. Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes before the onset of PARP cleavage in MSeA-exposed cells, experiments with phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage. Taken together, exposure of DU145 cells to MSeA versus selenite induced differential patterns of cell cycle arrest and apoptosis execution as well as distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely differentially targeted by selenium metabolite pools to mediate cancer chemoprevention.
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PMID:Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. 1248 29

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 natural history of prostate cancer is a multistage process that involves the transition from normal tissue to subclinical cancer, with progression to carcinoma in situ and eventually metastatic disease. Evidence suggests that a high-fat diet plays a critical role in the biology and progression of the disease. ACI rats were maintained for two generations on high beef fat or control diets for 18 months. Affymetrix microarrays were used to analyze the mRNA expression levels in the dorsolateral prostates of rats on the different diets. Approximately 4752 genes and expressed sequence tag (EST) were expressed in the prostates of rats on either diet. Twenty-seven genes were upregulated and 28 genes downregulated in the high beef fat diet. Data analysis indicated that a high beef fat diet affects the expression of genes involved in inflammation, glucose and fatty acid metabolism, androgen metabolism, potential tumor suppression and protein kinase activity, as well as intracellular and extracellular matrix molecules, growth factors and androgen responsive genes. Results from these and future studies will lead to a better understanding of the effect of diet on gene expression in the prostate and facilitate the rational design and assessment of potential dietary programs for prostate cancer prevention.
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PMID:Microarray analysis of diet-induced alterations in gene expression in the ACI rat prostate. 1257 Mar 33

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that elicits the increase of intracellular cAMP levels and protein kinase A activity in various cell systems. Here we show that the pattern of cAMP elevation triggered by PACAP is critical for the fate of LNCaP prostate cancer cells. We demonstrate that these cells express PACAP and its type 1 receptor. A short-term stimulation with PACAP, which generates a transient cAMP rise, induces proliferation of LNCaP cells through a protein kinase A-dependent activation of the MAPK cascade. On the contrary, we observed that chronic PACAP stimulation, giving rise to a sustained cAMP accumulation, leads to proliferation arrest and neuroendocrine differentiation. Moreover, PACAP stimulates phosphory-lation and activation of the cAMP response element binding transcription factor (CREB), and MAPK activation is necessary for its full transcriptional activity, indicating a direct involvement of cAMP response element in PACAP action. These findings demonstrate that a crucial event determining the outcome of prostatic cancer cells progression is the sustained vs. transient intracellular cAMP increase.
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PMID:Dual effect of pituitary adenylate cyclase activating polypeptide on prostate tumor LNCaP cells: short- and long-term exposure affect proliferation and neuroendocrine differentiation. 1263 48

Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth.
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PMID:Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms. 1265 11

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

PTEN (phosphatase and tensin homologue deleted on chromosome-10), a dual specificity phosphatase, is a tumor suppressor gene whose inactivation has been associated with many different types of cancer including prostate cancer. Prostate adenocarcinoma is one of the most commonly diagnosed malignancies afflicting the male population in both the United States and Europe. The frequency of PTEN inactivation appears to increase during the progression of prostatic cancer. The physical loss of the PTEN genetic locus in prostate cancer progression has been well characterized, however the molecular implication of this loss of PTEN remains enigmatic. The purpose of this review is to describe the functional role of PTEN in the molecular pathogenesis of prostatic disease. We review the function of PTEN discussing its association with the phosphoinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signal transduction pathways. Additionally, we discuss the role of PTEN in the regulation of apoptotic pathways involving the anti-apoptotic gene bcl-2 and the pro-apoptotic ligand TRAIL. We also review the mechanisms that can lead to the loss of PTEN function. We describe genetic inactivation including loss of heterozygosity, haploinsufficiency and mutation. We conclude by outlining epigenetic loss including methylation, post-translational modifications and oxidative stress.
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PMID:The role of PTEN in the progression and survival of prostate cancer. 1271 46

Protein kinase CK2 seems to play an essential role in cellular growth regulation as well as in apoptosis. By using a pair of prostate carcinoma cell lines which are either hormone-sensitive (LNCaP cells) or hormone-refractory (PC-3 cells) we analysed the contribution of protein kinase CK2 to their different growth behaviour as well as to apoptosis. We found the same amount of CK2 subunits in both cell lines although the enzymatic activity of CK2 was much higher in the hormone-refractory cells. These results for the first time show a correlation between the specific activity of protein kinase CK2 and specific growth properties of prostate cancer cells. The antiproliferative flavonoid apigenin led to an inhibition of the CK2 activity in both types of cells but only the hormone-sensitive LNCaP cells responded with apoptosis. Thus, these results demonstrate that a high CK2 activity is dispensable for growth and not necessary for a protection against apoptosis in hormone-refractory prostate cancer cells.
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PMID:Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells. 1273 92

Our results revealed that the blockade of epidermal growth factor receptor (EGFR) tyrosine kinase and protein kinase A (PKA) signaling pathways by specific inhibitors (PD153035 and Rp-cAMPs) leads to a synergistic inhibition of EGF- and serum-stimulated growth of human prostatic cancer cells (LNCaP, DU145 and PC3) concomitant with an arrest in the G1 phase of cellular cycle. Of particular interest, the combination of PD153035 and Rp-cAMPs also caused a more substantial apoptotic/necrotic death of these prostatic cancer cells as compared to drugs alone. Moreover, we observed that the inhibition of acidic sphingomyelinase and caspase cascades results in a marked reduction of DNA fragmentation and apoptotic death induced by PD153035, alone or in combination with Rp-cAMPs, in EGF stimulated PC3 cells. This suggests that these agents might mediate their cytotoxic effects at least in part via the ceramide generation and activation of caspase signaling pathways. N-oleoylethanolamine (OE), an inhibitor of acidic ceramidase, consistently potentiated the apoptotic effects of PD153035 in all the prostatic cancer cell lines tested. Additionally, the cellular ceramide content estimated for PC3 cells was increased after treatment with PD153035, alone or in combination, at a lower dose with OE and Rp-cAMPs. The synergistic apoptotic effect of PD153035 plus Rp-cAMPs induced in PC3 was also accompanied by a significant rate of mitochondrial membrane depolarization and release of cytochrome c into cytosol as compared to drugs alone. Combined, the results indicated that the simultaneous inhibition of EGFR and PKA signaling cascades might lead to a more massive apoptotic death of metastatic prostatic cancer cells by increasing ceramide accumulation and activating of caspase cascade of a mitochondrial dependent manner.
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PMID:Synergistic antiproliferative and apoptotic effects induced by epidermal growth factor receptor and protein kinase a inhibitors in human prostatic cancer cell lines. 1279 66


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