Interleukin-1α Mediates the Antiproliferative Effects of 1,25-Dihydroxyvitamin D3 in Prostate Progenitor/Stem Cells

Vitamin D-3 is a promising preventative and therapeutic agent for prostate cancer, but its implementation is hampered by a lack of understanding about its mechanism of action. Upon treatment with 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)(2)D-3, vitamin D-3], the metabolically active form of vitamin D-3, adult prostate progenitor/stem cells (PrP/SC) undergo cell-cycle arrest, senescence, and differentiation to an androgen receptor-positive luminal epithelial cell fate. Microarray analyses of control-and vitamin D-3-treated PrP/SCs revealed global gene expression signatures consistent with induction of differentiation. Interestingly, one of the most highly upregulated genes by vitamin D-3 was the proinflammatory cytokine interleukin-1 alpha (IL-1 alpha). Systems biology analyses supported a central role for IL-1 alpha in the vitamin D-3 response in PrP/SCs. siRNA-mediated knockdown of IL-1 alpha abrogated vitamin D-3-induced growth suppression, establishing a requirement for IL-1 alpha in the antiproliferative effects of vitamin D-3 in PrP/SCs. These studies establish a system to study the molecular profile of PrP/SC differentiation, proliferation, and senescence, and they point to an important new role for IL-1 alpha in vitamin D-3 signaling in PrP/SCs. Cancer Res; 71(15); 5276-86. (c) 2011 AACR.