Phytosterols impact prostate cell growth by enhanced expression of androgen-regulated genes.

A98

Recent data have shown ethnic variations in the expression pattern of some prostatic androgen regulated genes that have cell growth-promoting functions namely, NDRG1 and a prostate specific gene PCGEM1. These data may support the current lack of definitive molecular basis for the existing disparity in prostate cancer along ethnic lines. Moreover, the regulatory role of increased dietary fat intake in the maintenance of androgen homeostasis may, corroborate the suggested role of high fat intake with the high incidence and poor prognosis of prostate cancer in African-Americans The objective of this study is to show that phytosterols prevent prostate cancer, through the suppression of cholesterol-regulated downstream targets of prostate cell growth and /or apoptosis. Our working hypothesis is that cholesterol and phytosterols act on two genetic determinants of prostate cell growth and disease progression. Specifically, we evaluated the potential link between these sterols and prostate cell growth or apoptosis. We also, determined the effects of cholesterol on the expression of these biomarkers in various prostate cancer cell lines. In this study, genetic and molecular techniques were used to determine the expression of NDRG1 and PCGEM1 in control and sterol-supplemented prostate cancer cell lines. Also, the effects of the different sterols in prostate cell growth and apoptosis were evaluated by cell proliferation and DNA fragment end labeling methods respectively. To verify the apoptotic nature of phytosterols, coexpression of pro-apoptotic and anti-apoptotic genes (BclXL and BclXs respectively) in all the cell lines were performed by RT-PCR. Our study revealed that cholesterol modulates the transcription of NDRG1 and PCGEM1 in different prostate cancer cell lines. On the other hand, our results showed that phytosterols have contrasting effect. The interaction of cholesterol with genetic determinants of prostate cell growth and disease progression suggest that prostate neoplasm should be understood at the molecular level to develop effective nutritional prevention and intervention strategies that will control and prevent the malignancy. Identifying the genes that are responsive to sterol homeostasis may represent a major step in elucidating the mechanism underlying the impact of sterols on prostate cell growth or apoptosis. In view of the heterogeneous nature of prostate cancer in humans, these cholesterol-regulated markers may efficiently predict neoplasms that would be responsive to chemoprevention by phytosterols. Also, elucidation of the mechanism by which cholesterol mediate prostate cancer would strengthen the existing dogma that dietary fat plays a role in the disparity in prostate cancer incidence along ethnic lines. Finally, opposing patterns of apoptotic gene expression in response to sterols will determine their position as targets for prevention of prostate cancer.