Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3

被引:85
作者
Schwartz, GG
Eads, D
Rao, A
Cramer, SD
Willingham, MC
Chen, TC
Jamieson, DP
Wang, LL
Burnstein, KL
Holick, MF
Koumenis, C
机构
[1] Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA
[2] Wake Forest Univ, Bowman Gray Sch Med, Dept Urol, Winston Salem, NC 27157 USA
[3] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA
[4] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Ctr Comprehens Canc, Winston Salem, NC 27157 USA
[5] Boston Univ, Med Ctr, Vitamin D Skin & Bone Res Lab, Boston, MA 02118 USA
[6] Univ Miami, Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA
[7] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiat Oncol, Winston Salem, NC 27157 USA
关键词
D O I
10.1093/carcin/bgh086
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 [1alpha(OH)ase]. 1alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1alpha(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 1alpha(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.
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页码:1015 / 1026
页数:12
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