Molecular mechanism of sterol-induced signaling and disparity of prostate cancer incidence Free

A11

High prevalence and poor prognosis of prostate cancer in African Americans has been associated with high intake of saturated fats and cholesterol. The connection between obesity, dietary fat and aggressive prostate cancer is inferred from several retrospective and prospective studies of populations, animal experiments and limited clinical research on humans. The pathogenesis of prostate cancer by obesity is unclear and controversial. Nevertheless, lipid abnormalities, especially elevated circulating cholesterol, triglycerides and LDL cholesterol are common features of obesity and may be the contributing factors. The pathogenic mechanism for promotion of prostate cancer by cholesterol is unclear. Several studies show that cellular cholesterol trafficking favors it’s mixing with the bulk plasma membrane cholesterol. Membrane cholesterol enrichment is reportedly a trigger of signaling responses leading to cell growth and carcinogenesis. To the contrary, dietary phytosterols, which are plant cholesterol counterparts, have reportedly suppressive effects on cell growth and signaling. The objective of this study was to establish the molecular mechanism for sterol regulation of prostate cancer incidence and probably the basis for racial disparity in incidence of disease. We investigated the hypothesis that the differences in sterol promotion of prostate cancer can be attributed to differential signaling of caveolin1 (cav-1)-mediated oncogenes and growth-suppressors. The expression of these genes in cultured prostate cancer cell lines was genetically analyzed by RT-PCR. The effects of different sterols on prostate cell growth were analyzed with a Coulter counter, while mitosis and apoptosis were assayed by real RT-PCR and flow cytometry. Our study revealed that cholesterol enrichment promoted mitosis and cell growth, while phytosterols suppressed mitosis and significantly induced tumor-suppression and promoted apoptosis. We demonstrated for the first time that cholesterol upregulated the expression of an oncogene PCGEM1 even in androgen-insensitive prostate cancer cell lines. Phytosterols reversed this effect, while upregulating the expression of cav-1, a mediator of androgen-dependent proto-oncogene signals that control growth and apoptosis. Cholesterol also attenuated the co-expression of cav-1 and NDRG1 genes in both prostate cancer cell lines, while phytosterols reversed this effect. Similarity in the pattern of expression of cav-1 with oncogenes and growth-suppressors by these sterols suggests that cav-1 may mediate various signals of sterol-enrichment. Sterols may therefore contribute to the disparity in incidence of prostate cancer among racial groups by molecular mechanisms that involve cav-1 signaling of pro- and anti-apoptotic genes.