Vitamin D and testosterone co-ordinately modulate intracellular zinc levels and energy metabolism in prostate cancer cells

Vitamin D-3 and its receptor are responsible for controlling energy expenditure in adipocytes and have direct roles in the transcriptional regulation of energy metabolic pathways. This phenomenon also has a significant impact on the etiology of prostate cancer (PCa). Using several in vitro models, the roles of vitamin D-3 on energy metabolism and its implication in primary, early, and late invasive PCa were investigated. BODIPY staining and qPCR analyses show that 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) up-regulates de novo lipogenesis in PCa cells by orchestrating transcriptional regulation that affects cholesterol and lipid metabolic pathways. This lipogenic effect is highly dependent on the interaction of several nuclear receptors and their corresponding ligands, including androgen receptor (AR), vitamin D receptor (VDR), and retinoid X receptor (RXR). In contrast, inhibition of peroxisome proliferator-activated receptor alpha (PPAR alpha) signaling blocks the induction of the lipogenic phenotype induced by these receptors. Furthermore, 1,25(OH)(2)D-3, T, and 9 cis-retinoic acid (9-cis RA) together redirect cytosolic citrate metabolism toward fatty acid synthesis by restoring normal prostatic zinc homeostasis that functions to truncate TCA cycle metabolism. 1,25(OH)(2)D-3, T, and 9-cis RA also exert additional control of TCA cycle metabolism by down-regulating SLC25A19, which limits the availability of the co-factor thiamine pyrophosphate (TPP) that is required for enzymatic catalyzation of citrate oxidation. This extensive metabolic reprogramming mediated by 1,25(OH)(2)D-3, T, and 9-cis RA is preserved in all in vitro cell lines investigated. These data suggest that 1,25(OH)(2)D-3 and T are important regulators of normal prostatic energy metabolism. Based on the close association between energy metabolism and cancer progression, supplementation of vitamin D-3 and testosterone can restrict the energy production that is required to drive PCa progression by maintaining proper zinc homeostasis and inhibiting TCA cycle activity in PCa cells.