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

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.

[1]  K. Guyton,et al.  Cancer chemoprevention using natural vitamin D and synthetic analogs. , 2003, Annual review of pharmacology and toxicology.

[2]  D. Matallanas,et al.  Differences on the Inhibitory Specificities of H-Ras, K-Ras, and N-Ras (N17) Dominant Negative Mutants Are Related to Their Membrane Microlocalization* , 2003, The Journal of Biological Chemistry.

[3]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[4]  J. Rhim,et al.  Targeted Disruption of the 25-Hydroxyvitamin D3 1α-Hydroxylase Gene in ras-Transformed Keratinocytes Demonstrates That Locally Produced 1α,25-Dihydroxyvitamin D3 Suppresses Growth and Induces Differentiation in an Autocrine Fashion11 Canadian Institutes of Health Research Grant MT10839 (to R.K.). , 2002 .

[5]  M. Willingham,et al.  p27 Kip1 Is Essential for the Antiproliferative Action of 1,25-Dihydroxyvitamin D3 in Primary, but Not Immortalized, Mouse Embryonic Fibroblasts* , 2002, The Journal of Biological Chemistry.

[6]  M. Holick,et al.  25-Hydroxyvitamin D-1α-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[7]  H. Gogas,et al.  A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer , 2002, British Journal of Cancer.

[8]  S. Ryu,et al.  Enhanced apoptosis and radiosensitization by combined 13-CIS-retinoic acid and interferon-α2a; role of RAR-β gene , 2001 .

[9]  G. Miller,et al.  Growth inhibitory effects of 1alpha, 25-dihydroxyvitamin D(3) are mediated by increased levels of p21 in the prostatic carcinoma cell line ALVA-31. , 2001, Cancer research.

[10]  Donghui Li,et al.  Molecular epidemiology of pancreatic cancer , 2001, International journal of gastrointestinal cancer.

[11]  S. Leach,et al.  Developmental aspects of early pancreatic cancer. , 2001, Cancer journal.

[12]  D. Bar-Sagi,et al.  Differential Activation of the Rac Pathway by Ha-Ras and K-Ras* , 2001, The Journal of Biological Chemistry.

[13]  P. Fisher,et al.  Differentiation therapy of human cancer: basic science and clinical applications. , 2001, Pharmacology & therapeutics.

[14]  A. Kutner,et al.  Potentiation of the antiproliferative effect in vitro of doxorubicin, cisplatin and genistein by new analogues of vitamin D. , 2001, Anticancer research.

[15]  J. McNeal,et al.  Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. , 2001, Cancer research.

[16]  I. Schuster,et al.  Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D3: CYP27 in epidermis completes the set of essential vitamin D3-hydroxylases , 2001, Steroids.

[17]  E. Bajna,et al.  25-Hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis , 2001, Steroids.

[18]  A. Howie,et al.  Extrarenal Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase1 , 2001 .

[19]  D. Zehnder,et al.  1alpha-Hydroxylase and the action of vitamin D. , 2000, Journal of molecular endocrinology.

[20]  A. Rosemurgy,et al.  New directions in systemic therapy of pancreatic cancer. , 2000, Cancer control : journal of the Moffitt Cancer Center.

[21]  A. Dalgleish,et al.  Differential and antagonistic effects of 9- cis -retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro , 2000, British Journal of Cancer.

[22]  C. M. Hansen,et al.  Seocalcitol (EB 1089): a vitamin D analogue of anti-cancer potential. Background, design, synthesis, pre-clinical and clinical evaluation. , 2000, Current pharmaceutical design.

[23]  S. Cramer,et al.  25-Hydroxyvitamin D3, the prohormone of 1,25-dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[24]  K. Burnstein,et al.  The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  H. Koeffler,et al.  Effect of a novel vitamin D3 analog, EB1089, on G1 cell cycle regulatory proteins in HL-60 cells. , 2000, International journal of oncology.

[26]  D. Gewirtz,et al.  The vitamin D3 analog EB 1089 enhances the response of human breast tumor cells to radiation. , 1999, Radiation research.

[27]  N. Weigel,et al.  Vitamin D and Prostate Cancer , 1999, Journal of andrology.

[28]  M. Hewison,et al.  Constitutive Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase in a Transformed Human Proximal Tubule Cell Line: Evidence for Direct Regulation of Vitamin D Metabolism by Calcium. , 1999, Endocrinology.

[29]  G. Miller,et al.  1α,25-Dihydroxyvitamin D3 and Platinum Drugs Act Synergistically to Inhibit the Growth of Prostate Cancer Cell Lines , 1999 .

[30]  R. Koren,et al.  1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. , 1999, Cancer research.

[31]  M. Lipkin,et al.  Influence of dietary calcium and vitamin D on diet-induced epithelial cell hyperproliferation in mice. , 1999, Journal of the National Cancer Institute.

[32]  W. Miller.  The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer , 1998, Cancer.

[33]  G. Studzinski,et al.  Lowering of p27Kip1 levels by its antisense or by development of resistance to 1,25-dihydroxyvitamin D3 reverses the G1 block but not differentiation of HL60 cells , 1998, Leukemia.

[34]  R. Bouillon,et al.  Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells , 1998, Molecular and Cellular Endocrinology.

[35]  John H. White,et al.  Disruption of Vitamin D Receptor-Retinoid X Receptor Heterodimer Formation following ras Transformation of Human Keratinocytes* , 1998, The Journal of Biological Chemistry.

[36]  T. Chen,et al.  Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[37]  M. Campbell,et al.  Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. , 1997, Journal of molecular endocrinology.

[38]  F. Holmes.  Paclitaxel combination therapy in the treatment of metastatic breast cancer: a review. , 1996, Seminars in oncology.

[39]  S. Howell,et al.  Phase I Trial of Retinoic Acid and cis-Platinum for Advanced Squamous Cell Cancer of the Head and Neck Based on Experimental Evidence of Drug Synergism , 1996, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[40]  T. Nikaido,et al.  Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. , 1996, Gastroenterology.

[41]  Ahlgren Jd.  Epidemiology and risk factors in pancreatic cancer , 1996 .

[42]  L. Freedman,et al.  Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. , 1996, Genes & development.

[43]  H. Douglass,et al.  Adjuvant therapy for pancreatic cancer , 1995, World Journal of Surgery.

[44]  Z. Wang,et al.  Retinoic acid and acute promyelocytic leukemia: a model of targetting treatment for human cancer. , 1994, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[45]  G. Capellá,et al.  Pancreatic cancer in europe: Ki‐ras gene mutation pattern shows geographical differences , 1994, International journal of cancer.

[46]  E. Borden,et al.  Differentiation therapy of cancer: laboratory and clinical investigations. , 1993, Cancer research.

[47]  M. Haussler,et al.  Radioligand receptor assay for 25-hydroxyvitamin D2/D3 and 1 alpha, 25-dihydroxyvitamin D2/D3. , 1976, The Journal of clinical investigation.

[48]  A. Wellstein,et al.  The efficacy of 9-cis retinoic acid in experimental models of cancer , 2005, Breast Cancer Research and Treatment.

[49]  D. Thurnher,et al.  1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck. , 2001, Acta oto-laryngologica.

[50]  John H. White,et al.  Vitamin D Resistance in RAS-Transformed Keratinocytes: Mechanism and Reversal Strategies , 2001, Radiation research.

[51]  T. McDonnell,et al.  Calcitriol-Induced Apoptosis in LNCaP Cells Is Blocked By Overexpression of Bcl-21. , 2000, Endocrinology.

[52]  L. Binderup,et al.  Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. , 1997, British Journal of Cancer.

[53]  T. Nikaido,et al.  Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines. , 1997, British Journal of Cancer.

[54]  Uskoković Mr,et al.  Signaling pathways for vitamin D-induced differentiation: implications for therapy of proliferative and neoplastic diseases. , 1993 .