title: Interleukin-1α mediates the antiproliferative effects of 1,25-dihydroxyvitamin D3 in prostate progenitor/stem cells.
abstract: 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 1α,25-dihydroxyvitamin D(3) [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-1α (IL-1α). Systems biology analyses supported a central role for IL-1α in the vitamin D(3) response in PrP/SCs. siRNA-mediated knockdown of IL-1α abrogated vitamin D(3)-induced growth suppression, establishing a requirement for IL-1α 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-1α in vitamin D(3) signaling in PrP/SCs.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Maund
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Barclay
authors.forename: Laura D
authors.initials: LD
authors.lastname: Hover
authors.forename: Linara S
authors.initials: LS
authors.lastname: Axanova
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hipp
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D016161:Genes, Retinoblastoma; D019942:Genes, p16; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000166:cytology* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D053582:Interleukin-1alpha; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D002117:Calcitriol