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

Abstract Vitamin D3 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 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3, vitamin D3], the metabolically active form of vitamin D3, 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 D3–treated PrP/SCs revealed global gene expression signatures consistent with induction of differentiation. Interestingly, one of the most highly upregulated genes by vitamin D3 was the proinflammatory cytokine interleukin-1α (IL-1α). Systems biology analyses supported a central role for IL-1α in the vitamin D3 response in PrP/SCs. siRNA-mediated knockdown of IL-1α abrogated vitamin D3–induced growth suppression, establishing a requirement for IL-1α in the antiproliferative effects of vitamin D3 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-1α in vitamin D3 signaling in PrP/SCs. Cancer Res; 71(15); 5276–86. ©2011 AACR.