title: Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3.
abstract: The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1 alpha(OH)ase]. 1 alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1 alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D(3) inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D(3), indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D(3). The expression of 1 alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D(3) may offer possible therapeutic and chemopreventive options for pancreatic cancer.
authors.affiliation: Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Schwartz
authors.forename: Dawn
authors.initials: D
authors.lastname: Eads
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Jamieson
authors.forename: Lilin
authors.initials: L
authors.lastname: Wang
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Burnstein
authors.forename: Michael F
authors.initials: MF
authors.lastname: Holick
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D001483:Base Sequence; D002112:Calcifediol / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002112:Calcifediol