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

Gary Schwartz, Dawn Eads, Anuradha Rao, Scott D. Cramer, Mark C. Willingham, Tai C. Chen, Daniel P. Jamieson, Lilin Wang, Kerry L. Burnstein, Michael F. Holick, Constantinos Koumenis

Research output: Contribution to journalArticle

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Abstract

The steroid hormone 1,25-dihydroxyvitamin D3, [1,25(OH 2D3, 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 D3, the prohormone of 1,25(OH 2D3, is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-α-hydroxylase [1α(OH)ase]. 1α(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1α(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 D3 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 G1/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)D3, 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)D3. The expression of 1α(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D3 may offer possible therapeutic and chemopreventive options for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1015-1026
Number of pages12
JournalCarcinogenesis
Volume25
Issue number6
DOIs
StatePublished - Jun 1 2004

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Calcifediol
Mixed Function Oxygenases
Pancreatic Neoplasms
Calcitriol
Hormones
Cell Line
Growth
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
G1 Phase Cell Cycle Checkpoints
Mutation
Hypercalcemia
Enzymes
Tumor Cell Line
Vitamin D
Prostate
Colon
Adenocarcinoma
Immunohistochemistry
Alleles

ASJC Scopus subject areas

  • Cancer Research

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Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. / Schwartz, Gary; Eads, Dawn; Rao, Anuradha; Cramer, Scott D.; Willingham, Mark C.; Chen, Tai C.; Jamieson, Daniel P.; Wang, Lilin; Burnstein, Kerry L.; Holick, Michael F.; Koumenis, Constantinos.

In: Carcinogenesis, Vol. 25, No. 6, 01.06.2004, p. 1015-1026.

Research output: Contribution to journalArticle

Schwartz, G, Eads, D, Rao, A, Cramer, SD, Willingham, MC, Chen, TC, Jamieson, DP, Wang, L, Burnstein, KL, Holick, MF & Koumenis, C 2004, 'Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3', Carcinogenesis, vol. 25, no. 6, pp. 1015-1026. https://doi.org/10.1093/carcin/bgh086
Schwartz, Gary ; Eads, Dawn ; Rao, Anuradha ; Cramer, Scott D. ; Willingham, Mark C. ; Chen, Tai C. ; Jamieson, Daniel P. ; Wang, Lilin ; Burnstein, Kerry L. ; Holick, Michael F. ; Koumenis, Constantinos. / Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. In: Carcinogenesis. 2004 ; Vol. 25, No. 6. pp. 1015-1026.
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abstract = "The steroid hormone 1,25-dihydroxyvitamin D3, [1,25(OH 2D3, 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 D3, the prohormone of 1,25(OH 2D3, is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-α-hydroxylase [1α(OH)ase]. 1α(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1α(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 D3 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 G1/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)D3, 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)D3. The expression of 1α(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D3 may offer possible therapeutic and chemopreventive options for pancreatic cancer.",
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T1 - Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3

AU - Schwartz, Gary

AU - Eads, Dawn

AU - Rao, Anuradha

AU - Cramer, Scott D.

AU - Willingham, Mark C.

AU - Chen, Tai C.

AU - Jamieson, Daniel P.

AU - Wang, Lilin

AU - Burnstein, Kerry L.

AU - Holick, Michael F.

AU - Koumenis, Constantinos

PY - 2004/6/1

Y1 - 2004/6/1

N2 - The steroid hormone 1,25-dihydroxyvitamin D3, [1,25(OH 2D3, 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 D3, the prohormone of 1,25(OH 2D3, is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-α-hydroxylase [1α(OH)ase]. 1α(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1α(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 D3 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 G1/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)D3, 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)D3. The expression of 1α(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D3 may offer possible therapeutic and chemopreventive options for pancreatic cancer.

AB - The steroid hormone 1,25-dihydroxyvitamin D3, [1,25(OH 2D3, 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 D3, the prohormone of 1,25(OH 2D3, is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-α-hydroxylase [1α(OH)ase]. 1α(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1α(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 D3 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 G1/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)D3, 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)D3. The expression of 1α(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D3 may offer possible therapeutic and chemopreventive options for pancreatic cancer.

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