Cholesterol and prostate cancer.
Cholesterol is a neutral lipid that accumulates in liquid-ordered, detergent-resistant membrane domains called lipid rafts. Lipid rafts serve as membrane platforms for signal transduction mechanisms that mediate cell growth, survival, and a variety of other processes relevant to cancer. A number of studies, going back many years, demonstrate that cholesterol accumulates in solid tumors and that cholesterol homeostasis breaks down in the prostate with aging and with the transition to the malignant state. This review summarizes the established links between cholesterol and prostate cancer (PCa), with a focus on how accumulation of cholesterol within the lipid raft component of the plasma membrane may stimulate signaling pathways that promote progression to hormone refractory disease. We propose that increases in cholesterol in prostate tumor cell membranes, resulting from increases in circulating levels or from dysregulation of endogenous synthesis, results in the coalescence of raft domains. This would have the effect of sequestering positive regulators of oncogenic signaling within rafts, while maintaining negative regulators in the liquid-disordered membrane fraction. This approach toward examining the function of lipid rafts in prostate cancer cells may provide insight into the role of circulating cholesterol in malignant growth and on the potential relationship between diet and aggressive disease. Large-scale characterization of proteins that localize to cholesterol-rich domains may help unveil signaling networks and pathways that will lead to identification of new biomarkers for disease progression and potentially to novel targets for therapeutic intervention.
Freeman
Michael R
MR
The Urological Diseases Research Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA. michael.freeman@tch.harvard.edu
Solomon
Keith R
KR
D000214:Acyl Coenzyme A / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000214:Acyl Coenzyme A; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D002784:Cholesterol