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)

Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in cell membranes that regulate phosphorylation cascades originating from membrane-bound proteins. In this study, we tested whether alteration of the cholesterol content of lipid rafts in prostate cancer (PCa) cell membranes affects cell survival mechanisms in vitro and in vivo. Simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, inhibited Akt1 serine-threonine kinase (protein kinase Balpha)/protein kinase B (Akt/PKB) pathway signaling, and induced apoptosis in caveolin- and PTEN-negative LNCaP PCa cells. Replenishing cell membranes with cholesterol reversed these inhibitory and apoptotic effects. Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin. Elevation of circulating cholesterol in SCID mice increased the cholesterol content and the extent of protein tyrosine phosphorylation in lipid rafts isolated from LNCaP/sHB xenograft tumors. Cholesterol elevation also promoted tumor growth, increased phosphorylation of Akt, and reduced apoptosis in the xenografts. Our results implicate membrane cholesterol in Akt signaling in both normal and malignant cells and provide evidence that PCa cells can become dependent on a cholesterol-regulated Akt pathway for cell survival.
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PMID:Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. 1577 12

Lipid rafts/caveolae are membrane platforms for signaling molecules that regulate various cellular functions, including cell survival. To better understand the role of rafts in tumor progression and therapeutics, we investigated the effect of raft disruption on cell viability and compared raft levels in human cancer cell lines versus their normal counterparts. Here, we report that cholesterol depletion using methyl-beta cyclodextrin caused anoikis-like apoptosis, which in A431 cells involved decreased raft levels, Bcl-xL down-regulation, caspase-3 activation, and Akt inactivation regardless of epidermal growth factor receptor activation. Cholesterol repletion replenished rafts on the cell surface and restored Akt activation and cell viability. Moreover, the breast cancer and the prostate cancer cell lines contained more lipid rafts and were more sensitive to cholesterol depletion-induced cell death than their normal counterparts. These results indicate that cancer cells contain increased levels of rafts and suggest a potential use of raft-modulating agents as anti-cancer drugs.
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PMID:Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. 1656 87

The aim of the study was to establish whether metabolic syndrome predicts the incidence of prostate cancer. The hypothesis was tested using the 27-year follow-up of the prospective cohort of 16,209 men aged 40-49 years who participated in the Oslo Study in 1972-1973. Men with established diabetes and men with cancer diagnosed before screening were excluded, leaving 15,933 for analyses. Metabolic syndrome is here composed of body mass index, nonfasting glucose, triglycerides, and blood pressure or drug-treated hypertension. Two analytical approaches were compared, namely, predefined (adjusted from National Cholesterol Education Program) and quartile values of risk factors. Age, body mass index, and sedentary versus intermediate physical activity at work were significant predictors in univariate proportional hazards regression analyses. Combinations of any two (relative risk = 1.23; p = 0.04) or any three (relative risk = 1.56; p = 0.00) factors of the metabolic syndrome using quartile values of risk factors were predictive of prostate cancer. The number of cases for four factors was too small for analyses. Predefined values of the risk factors were not found to be predictive. In conclusion, metabolic syndrome was found to predict prostate cancer during 27 years of follow-up, indicating an association between insulin resistance and the incidence of prostate cancer.
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PMID:Metabolic syndrome predicts prostate cancer in a cohort of middle-aged Norwegian men followed for 27 years. 1695 29

The functional consequences of changes in membrane lipid composition that coincide with malignant growth are poorly understood. Sufficient data have been acquired from studies of lipid binding proteins, post-translational modifications of signaling proteins, and biochemical inhibition of lipidogenic pathways to indicate that growth and survival pathways might be substantially re-directed by alterations in the lipid content of membranes. Cholesterol and glycosphingolipids segregate into membrane patches that exhibit a liquid-ordered state in comparison to membrane domains containing relatively lower amounts of these classes of lipids. These "lipid raft" structures, which may vary in size and stability in different cell types, both accumulate and exclude signaling proteins and have been implicated in signal transduction through a number of cancer-relevant pathways. In prostate cancer cells, signaling from epidermal growth factor receptor (EGFR) to the serine-threonine kinase Akt1, as well as from IL-6 to STAT3, have been demonstrated to be influenced by experimental interventions that target cholesterol homeostasis. The recent finding that classical steroid hormone receptors also reside in these microdomains, and thus may function within these structures in a signaling capacity independent of their role as nuclear factors, suggests a novel means of cross-talk between receptor tyrosine kinase-derived and steroidogenic signals. Potential points of intersection between components of the EGFR family of receptor tyrosine kinases and androgen receptor signaling pathways, which may be sensitive to disruptions in cholesterol metabolism, are discussed. Understanding the manner in which these pathways converge within cholesterol-rich membranes may present new avenues for therapeutic intervention in hormone-dependent cancers.
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PMID:Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes. 1717 42

Cells maintain normal structure and function by responding appropriately to cues from the surrounding milieu. Extracellular stimuli are transduced from the surface through the plasma membrane by a complex series of interactions between ligands, their receptors and intracellular signaling partners (e.g., kinases, G proteins). Cholesterol-enriched membrane microdomains, generally referred to as "lipid rafts", exist within the lipid bilayer of all mammalian cells and play an important role in signaling from the cell surface to various subcellular compartments. Lipid rafts have also been implicated in tumor growth and aggressiveness. Epidemiological evidence suggests that the modern Western diet, which contains substantial levels of cholesterol and other fatty substances, promotes prostate cancer progression. Consistent with this idea, prolonged inhibition of the cholesterol synthesis pathway by pharmacologic intervention in men has recently been associated with reduction in risk of advanced prostate cancer. In this review, we discuss the possibility that membrane cholesterol promotes prostate cancer progression by a mechanism that involves dysregulation of lipid raft-resident signaling complexes. This hypothesis provides new avenues for mechanistic studies as well as therapeutic intervention.
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PMID:Cholesterol and cholesterol-rich membranes in prostate cancer: an update. 1911 35

Statin drugs appear to protect against advanced and possibly high-grade prostate cancer, perhaps through cholesterol-lowering. Thus, we evaluated the association between plasma cholesterol and prostate cancer. We conducted a prospective study in the CLUE II cohort of Washington County, MD. Included were 6,816 male county residents aged 35+ years old who did not have a cancer diagnosis at baseline in 1989. Plasma cholesterol, measured enzymatically at baseline, was categorized by clinical cutpoints. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total (n = 438) and high-grade (Gleason sum > or =7, n = 137) prostate cancer. Compared to men with high cholesterol (> or =240 mg/dl), men with desirable (<200 mg/dl) or borderline (200 to <240 mg/dl) levels were less likely to develop high-grade prostate cancer, particularly when restricting to organ-confined cases (HR: 0.68, 95% CI 0.40-1.18; P trend = 0.12) and among men with higher BMI (HR: 0.36, 95% CI 0.16-0.79; P trend = 0.02). Results were unchanged after excluding cholesterol-lowering drug users. Cholesterol was not associated with total prostate cancer. Our study supports two prior ones suggesting that cholesterol influences risk of high-grade prostate cancer, and indirectly supports the hypothesis that cholesterol-lowering is a mechanism by which statins are protective.
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PMID:Association between plasma total cholesterol concentration and incident prostate cancer in the CLUE II cohort. 1980 65

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non-users of statins or other cholesterol-lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996-2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate-specific antigen (PSA) level was compared between current users and non-users of cholesterol-lowering drugs. Compared with medication non-users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63-0.89]. The inverse association was dose-dependent with cumulative amount of statin use, and strongest for low-grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol-lowering drugs (HR 0.62, 95% CI 0.28-1.38), but without dose-dependence. Age-adjusted median serum PSA tended to be lower among users of cholesterol-lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non-users was eliminated by systematical prostate cancer screening. Cholesterol-lowering with statins seems beneficial for prostate cancer prevention.
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PMID:Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trial. 2007 66

The primary risk-modifying factors for prostate cancer are still a matter of debate. This work proposes and examines the hypothesis that the apolipoprotein E epsilon4 (ApoE4) allele and diet are important risk factors for prostate cancer. The hypothesis was evaluated in an ecological study involving 122 countries for which prostate cancer rates for 2002, ApoE4 allele prevalence, dietary supply values, and per capita gross domestic product (GDP) data were available, and for which there were at least 250,000 inhabitants. In addition, a subset of 102 countries with ApoE4 prevalence of less than 30% was also used. In the full data set, per capita GDP, lack of cereal consumption, milk protein and ApoE4 were significantly correlated with incidence, explaining 60% of the variance. In the 102-country subset of 102, per capita GDP, ApoE4 prevalence, and milk protein explained 62% of the variance of prostate cancer incidence, while lack of cereal consumption, ApoE4 prevalence and per capita GDP explained 55% of the variance of prostate cancer mortality rates. Cholesterol has been identified as an important risk factor for prostate cancer. The ApoE4 allele increases cholesterol production and cereal consumption lowers serum cholesterol levels. The ApoE4 allele is an important risk factor for Alzheimer's disease, and cholesterol is a risk factor and cereals a risk reduction factor. The ApoE4-diet-GDP hypothesis may explain the higher risk of prostate cancer for African Americans and should form the basis for further studies.
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PMID:A multicountry ecological study of risk-modifying factors for prostate cancer: apolipoprotein E epsilon4 as a risk factor and cereals as a risk reduction factor. 2015 Jun 35

Cholesterol is a structural component of lipid rafts within the plasma membrane. These domains, used as platforms for various signaling molecules, regulate cellular processes including cell survival. Cholesterol contents are tightly correlated with the structure and function of lipid rafts. Liver X receptors (LXRs) have a central role in the regulation of cholesterol homeostasis within the cell. Therefore, we investigated whether these nuclear receptors could modulate lipid raft signaling and consequently alter prostate cancer (PCa) cell survival. Treatment with the synthetic LXR agonist T0901317 downregulated the AKT survival pathway and thus induced apoptosis of LNCaP PCa cells in both xenografted nude mice and cell culture. The decrease in tumor cholesterol content resulted from the upregulation of ABCG1 and the subsequent increase in reverse cholesterol transport. RNA interference experiments showed that these effects were mediated by LXRs. Atomic force microscopy scanning of the inner plasma membrane sheet showed smaller and thinner lipid rafts after LXR stimulation, associated with the downregulation of AKT phosphorylation in these lipid rafts. Replenishment of cell membranes with exogenous cholesterol antagonized these effects, showing that cholesterol is a key modulator in this process. Altogether, pharmacological modulation of LXR activity could thus reduce prostate tumor growth by enhancing apoptosis in a lipid raft-dependent manner.
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PMID:Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. 2019 Aug 11

The field of the potential applications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) beyond their unambiguous cardiovascular beneficial effects is steadily increasing. In this regard, statins have also been shown to possess anti-inflammatory, immunomodulatory, antioxidant and growth inhibitory properties. Regarding their role in carcinogenesis, both preclinical and clinical studies report conflicting results. Intriguingly, accumulating evidence suggests that statins may relate to decreased prostate cancer incidence and recurrence risk. However, data from clinical studies seem to be still weak and are confounded by several factors. Nonetheless, preclinical data suggest that statins might exert a chemopreventive role against prostate cancer by inhibiting the proliferation and inducing apoptosis of prostate cancer cells and also inhibiting angiogenesis, inflammation and metastasis. Cholesterol lowering as well as statin pleiotropy through inhibition of the synthesis of isoprenoids have both been implicated in their anticancer properties. In this review, we discuss the preclinical and clinical evidence supporting the preventive or potentially harmful effects of statins on prostate tumourigenesis and conclude that statins should not be recommended for the prevention of prostate cancer development or progression based on the current data.
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PMID:Statins and prostate cancer: molecular and clinical aspects. 2135 84


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