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 (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/SC revealed global gene expression signatures consistent with induction of differentiation. Interestingly, one of the most highly-upregulated genes by vitamin D3 was the pro-inflammatory cytokine interleukin-1 alpha (IL1α). Systems biology analyses supported a central role for IL1α in the vitamin D3 response in PrP/SC. siRNA-mediated knockdown of IL1α abrogated vitamin D3-induced growth suppression, establishing a requirement for IL1α in the anti-proliferative effects of vitamin D3 in PrP/SC. 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 IL1α in vitamin D3 signaling in prostate progenitor/stem cells.

The Role of Vitamin D in the Prevention and Treatment of Prostate Cancer

“…AR signaling plays critical roles in prostate development, function, and pathogenesis. We reported that prostate progenitor/stem cells are AR-negative but, upon treatment with 1,25(OH) 2 D 3 , they become AR-positive (Barclay et al, 2008;Maund, et al, 2011). AR is not a direct transcriptional target of 1,25(OH) 2 D 3 because it does not contain a VDRE, but we did observe increased AR mRNA in response to 1,25(OH) 2 D 3 ; its mechanism of upregulation is unclear (Zhao, et al, 1999).…”

“…Agents that limit this capacity and promote differentiation are promising chemopreventative agents. We have recently reported that 1,25(OH) 2 D 3 is growth-inhibitory in adult prostate stem/progenitor cells (Maund, et al, 2011). 1,25(OH) 2 D 3 can induce G1 and G2 cell cycle arrest, stimulate differentiation toward a luminal epithelial cell type, and trigger senescence in this cell population, supporting a relevant role for vitamin D 3 in prostate chemoprevention (particularly in light of the cancer stem cell hypothesis).…”

“…In the C4-2 prostate cancer cell line, 1,25(OH) 2 D 3 inhibited cMYC which subsequently suppressed E2F activity and cell cycle progression regardless of pRB status (Washington et al, 2011). We have reported that 1,25(OH) 2 D 3 induces cell cycle arrest independently from pRB in prostate progenitor/stem cells (Maund et al, 2011). Flores and Burnstein recently reported that the cell cycle inhibitory protein GADD45 mediates 1,25(OH) 2 D 3 -induced accumulation of LNCaP cells in G1 (Flores & Burnstein, 2010).…”

“…Cell cycle arrest in G1 is a common downstream effect of 1,25(OH) 2 D 3 treatment, and additional mechanisms of cell cycle regulation by 1,25(OH) 2 D 3 are still being uncovered. 1,25(OH) 2 D 3 can induce differentiation of several cell types including prostate stem cells, prostate epithelial cells and prostate cancer cells (Miller et al, 1992;Tokar & Webber, 2005;Maund, et al, 2011). Differentiated prostate cells do not normally divide, so 1,25(OH) 2 D 3 may slow or halt any aberrant cell division.…”

“…We found that the cytokine interleukin-1 alpha is highly upregulated by 1,25(OH) 2 D 3 and is a novel mediator of 1,25(OH) 2 D 3 -induced growth inhibition of prostate stem/progenitor cells. In addition, microarray data revealed that 1,25(OH) 2 D 3 can impact gene expression and signalling pathways involved in stem cell self-renewal and multilineage differentiation including Hedgehog, Wnt, and TGF signaling (Maund, et al, 2011). 1,25(OH) 2 D 3 regulates components of these pathways in other cell types as well (Sarkar et al, 2010;Tang et al, 2011).…”