Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 PTEN/MMAC1 phosphatase is a tumor suppressor gene implicated in a wide range of human cancers. Here we provide biochemical and functional evidence that PTEN/MMAC1 acts a negative regulator of the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway. PTEN/MMAC1 impairs activation of endogenous Akt in cells and inhibits phosphorylation of 4E-BP1, a downstream target of the PI3-kinase/Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN/MMAC1 mutant enhances 4E-BP1 phosphorylation. In addition, PTEN/MMAC1 represses gene expression in a manner that is rescued by Akt but not PI3-kinase. Finally, higher levels of Akt activation are observed in human prostate cancer cell lines and xenografts lacking PTEN/MMAC1 expression when compared with PTEN/MMAC1-positive prostate tumors or normal prostate tissue. Because constitutive activation of either PI3-kinase or Akt is known to induce cellular transformation, an increase in the activation of this pathway caused by mutations in PTEN/MMAC1 provides a potential mechanism for its tumor suppressor function.
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PMID:The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. 986 Oct 13

Recent analyses indicate that the expression of the Pim-1 protein kinase is elevated in biopsies of prostate tumors. To identify the mechanism by which the Pim kinases may affect the growth of prostate tumors, we expressed Pim-1, Pim-2, or a kinase-dead Pim-2 protein in human PC3 prostate cancer cells. On implantation of the transfectants in nude mice, the growth of the cells expressing Pim-1 or Pim-2 was significantly faster than the growth of the control cells transfected with the neomycin-resistant gene or the kinase-dead Pim-2 protein. When grown in medium, the doubling time of the Pim-1 and Pim-2 transfectants was faster (0.75 days) than that of the control cells (1.28 days). We, therefore, examined the ability of Pim to control the phosphorylation of proteins that regulate protein synthesis. On growth factor starvation or rapamycin treatment, the Pim-1 and Pim-2 transfectants maintained their ability to phosphorylate 4E-BP1 and S6 kinase, although this phosphorylation did not occur in the control-transfected PC3 cells. We have found that the cellular levels of c-Myc were elevated in the Pim-1 and Pim-2 transfectants under these conditions. The Pim-1 and Pim-2 transfectants have lower levels of serine/threonine protein phosphatase 2A (PP2A) activity and the alpha- and beta-subunit B56gamma of the PP2A phosphatase do not coimmunoprecipitate in these cells. Thus, the effects of Pim on PP2A activity may mediate the levels of c-Myc and the phosphorylation of proteins needed for increased protein synthesis. Both of these changes could have a significant impact on tumor growth.
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PMID:Pim family kinases enhance tumor growth of prostate cancer cells. 1612 40

Androgen receptor (AR) plays a central role in prostate cancer, with most tumors responding to androgen deprivation therapies, but the molecular basis for this androgen dependence has not been determined. Androgen [5alpha-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression. However, cyclin D1 and D2 message levels were unchanged, indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism. This mechanism was identified as mammalian target of rapamycin (mTOR) activation. DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins. Significantly, DHT stimulation of mTOR was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase. In contrast, mTOR activation by DHT was dependent on AR-stimulated mRNA synthesis. Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions. These results indicate that a critical function of AR in PTEN-deficient prostate cancer cells is to support the pathologic activation of mTOR, possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of mTOR.
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PMID:Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. 1688 82

Phenethyl isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables, exerts significant protection against chemically induced cancer in animal models and inhibits growth of cancer cells in culture and in vivo by causing cell cycle arrest and apoptosis induction. In this study, we report a novel response to PEITC involving the regulation of translation initiation at pharmacologically achievable concentrations. Treatment of human colorectal cancer HCT-116 cells and human prostate cancer PC-3 cells, but not a normal prostate epithelial cell line (PrEC), with PEITC caused an increase in expression of the eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) and inhibition of 4E-BP1 phosphorylation. Results from pull-down assay using 7-methyl-GTP Sepharose 4B beads indicated that PEITC treatment reduced cap-bound eIF4E, confirming that increased 4E-BP1 expression and inhibition of 4E-BP1 phosphorylation indeed reduced the availability of eIF4E for translation initiation. Accordingly, results from in vivo translation using luciferase reporter assay indicated that PEITC treatment inhibited cap-dependent translation, in particular the translation of mRNA with secondary structure (stem-loop structure). Ectopic expression of eIF4E prevented PEITC-induced translation inhibition and conferred significant protection against PEITC-induced apoptosis. These results indicate that PEITC modulates availability of eIF4E for translation initiation leading to inhibition of cap-dependent translation. The present study also suggests that inhibition of cap-dependent translation may be an important mechanism in PEITC-induced apoptosis.
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PMID:Phenethyl isothiocyanate, a cancer chemopreventive constituent of cruciferous vegetables, inhibits cap-dependent translation by regulating the level and phosphorylation of 4E-BP1. 1744 67

We have shown previously that interleukin-8 (IL-8) and IL-8 receptor expression is elevated in tumor cells of human prostate biopsy tissue and correlates with increased cyclin D1 expression. Using PC3 and DU145 cell lines, we sought to determine whether IL-8 signaling regulated cyclin D1 expression in androgen-independent prostate cancer (AIPC) cells and to characterize the signaling pathways underpinning this response and that of IL-8-promoted proliferation. Administration of recombinant human IL-8 induced a rapid, time-dependent increase in cyclin D1 expression in AIPC cells, a response attenuated by the translation inhibitor cycloheximide but not by the RNA synthesis inhibitor, actinomycin D. Suppression of endogenous IL-8 signaling using neutralizing antibodies to IL-8 or its receptors also attenuated basal cyclin D1 expression in AIPC cells. Immunoblotting using phospho-specific antibodies confirmed that recombinant human IL-8 induced rapid time-dependent phosphorylation of Akt and the mammalian target of rapamycin substrate proteins, 4E-BP1 and ribosomal S6 kinase, resulting in a downstream phosphorylation of the ribosomal S6 protein (rS6). LY294002 and rapamycin each abrogated the IL-8-promoted phosphorylation of rS6 and attenuated the rate of AIPC cell proliferation. Our results indicate that IL-8 signaling (a) regulates cyclin D1 expression at the level of translation, (b) regulates the activation of proteins associated with the translation of capped and 5'-oligopyrimidine tract transcripts, and (c) activates signal transduction pathways underpinning AIPC cell proliferation. This study provides a molecular basis to support the correlation of IL-8 expression with that of cyclin D1 in human prostate cancer and suggests a mechanism by which this chemokine promotes cell proliferation.
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PMID:Interleukin-8 signaling promotes translational regulation of cyclin D in androgen-independent prostate cancer cells. 1760 77

Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy.
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PMID:eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. 1938 15

The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC(50) values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH(3) protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G(1)-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27(Kip1), a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells.
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PMID:Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells. 1950 54

Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
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PMID:MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. 1977 38

Diet and obesity, and their associated metabolic alterations, are some of the fastest-growing causes of disease and death in America. Findings from epidemiological studies correlating obesity, the sources of dietary fat and prostate cancer (PCa) are conflicting. We have previously shown that 15% of PB-ErbB-2 x pten(+/-) mice developed PCa and exhibited increased phosphorylated 4E-BP1, but not the key PI3-kinase intermediary phospho-protein, mTOR, when maintained on unrefined mouse chow. We report herein that 100% of animals fed refined, westernized AIN-93-based diets containing corn oil developed PCa by 12 months of age. Increases in visceral fat and mTO R activation in the tumors were also observed. Furthermore, nuclear cyclin E levels were significantly induced by the AIN-93-corn oil-based diets versus chow. Replacing 50% of the corn oil with menhaden oil, with 21% of its triglycerides being n-3 PUFA's, had no effect on tumorigenesis, fat deposition, cyclin E or mTOR. Phosphorylated BAD levels were similar in the tumors of mice in all three diets. Our data demonstrated that in the context of our preclinical model, components of crude chow, but not dietary n-3 PUFAs, protect against PCa progression. In addition, these data establish phosphorylated mTOR, nuclear cyclin E and visceral fat deposits as possible biomarkers of increased dietary risk for PCa.
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PMID:Dietary n-3 polyunsaturated fatty acids fail to reduce prostate tumorigenesis in the PB-ErbB-2 x Pten(+/-) preclinical mouse model. 2040 14

Metformin is a biguanine, the most widely used antidiabetic drug for the treatment of type 2 diabetes. Some studies suggest that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. Metformin activates the AMP-activated protein kinase (AMPK) pathway, a major sensor of the energy status of the cell and an inhibitor of mammalian target of rapamycin (mTOR) catalytic activity, inducing a decrease in blood glucose by decreasing hepatic gluconeogenesis and stimulating glucose uptake in the muscle. Some preclinical data supports the inhibition of tumour cancer cell growth associated with mTOR inhibition and a decrease in phosphorylation of S6K, rpS6 and 4E-BP1. Here we have summarised some of the preclinical data and data of many clinical trials that are exploring the true value of metformin for cancer patients, mainly breast and prostate cancer.
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PMID:Metformin: a new option in cancer treatment. 2168 Feb 96


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