Vitamin D and prostate cancer: Chemoprevention and chemoresistance
Abstract
High vitamin D status (serum 25-hydroxyvitamin D, 25 (OH)D) is associated with decreased prostate cancer (PCa) risk and 1 α, 25 dihydroxyvitamin D (1,25 (OH)2D, the biologically active form of vitamin D) exerts anti-cancer actions in both PCa cells and normal prostate epithelial cells (PEC). In an attempt to understand the role of vitamin D in the prevention of PCa, we first investigated 1,25 (OH)2D-induced target gene (CYP24 and TRPV6) expression in prostate cells. Our data from in vitro and in vivo studies demonstrated that compared to intestine, the classic target tissue of vitamin D, prostate exhibited a much less response to circulating 1,25 (OH)2D, indicating a possible role of locally synthesized 1,25 (OH)2D, instead of circulating 1,25 (OH)2D, in the regulation of prostate biology. Using androgen depletion/repletion model, we showed that dietary vitamin D significantly regulated the proliferation and apoptosis of PEC in a serum 25 (OH)D-dependent manner. PEC proliferation was increased and apoptosis was decreased in mice fed on vitamin D deficiency diet, while opposite effects were observed in mice on a pharmacological dose of vitamin D. Vitamin D actions are less potent in Apt 121 mice, a prostate cancer model, compared to the wild-type control, suggesting a decreased response to vitamin D in cancer cells. In order to further to address this question, we compared the response to 1,25 (OH)2D between cultured human PEC (RWPE1) and Ki-Ras transformed RWPE2 cells. Our data demonstrated that as a common contributor to cancer, Ki-ras transformation significantly abrogated the transcriptional and anti-cancer actions of 1,25 (OH)2D by phosphorylation of critical amino acids in the retinoid X receptor activation function 1 domain and impairing co-activator (SRC-1) recruitment. In all, our data support the hypothesis that dietary vitamin D can prevent prostate cancer through the local activation of 1,25 (OH)2D. Moreover, carcinogenesis-related molecular changes (i.e. Ki-Ras transformation) may alter their sensitivity to vitamin D.
Degree
Ph.D.
Advisors
Fleet, Purdue University.
Subject Area
Nutrition
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.