| The objectives of this study were to examine: (i) the potential of cholecalciferol (vitamin D3) as an agent for treatment by inhibiting or reversing malignant characteristics of prostate cancer cells; (ii) its ability as a chemoprevention agent by reversing cellular changes associated with malignant transformation, and (iii) its mechanisms of action. Because cholecalciferol can inhibit cellular changes associated with malignant transformation and invasion, I propose that cholecalciferol may be an effective agent for treatment, and for secondary and tertiary prevention of prostate cancer.; Chemoprevention is the ultimate answer to reducing the high incidence of prostate cancer. The ability of cholecalciferol, to block or reverse changes associated with malignant transformation, was examined. Since immortalization is an early step in carcinogenesis, the immortalized but non-tumorigenic RWPE-1 human prostate epithelial cell line was used. RWPE-1 cells do not grow in agar and are not invasive. Physiological levels of cholecalciferol: (i) inhibited anchorage-dependent growth; (ii) decreased MMP-9 and MMP-2 activity; (iii) induced differentiation by decreasing vimentin but increasing PSA expression, and (iv) up-regulated VDR, RXRs, and AR, suggesting that its effects, in part, are receptor-mediated. Based on these in vitro studies, cholecalciferol appears to be an effective chemopreventive agent. I further show that RWPE-1 cells also express CPYP27A1, and its expression is up-regulated by cholecalciferol. Since the presence of 1alpha-hydroxylase has previously been shown, my results demonstrate that human prostate epithelial cells, target cells for vitamin D, have the necessary enzymes and the rare ability to locally produce the biologically active calcitriol from cholecalciferol. The mechanisms of action of cholecalciferol appear to involve the up-regulation of nuclear receptors and CYP27A1. Taken together, my results show that cholecalciferol may be an effective agent for chemoprevention and treatment of prostate cancer. (Abstract shortened by UMI.)... |
