This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moreno, J. Articles by Feldman, D. Search for Related Content PubMed PubMed Citation Articles by Moreno, J. Articles by Feldman, D.

Regulation of Prostaglandin Metabolism by Calcitriol Attenuates Growth Stimulation in Prostate Cancer Cells

Departments of ¹ Medicine and ² Urology, Stanford University School of Medicine, Stanford, California

Requests for reprints: David Feldman, Stanford University School of Medicine, Room S025, 300 Pasteur Drive, Stanford, CA 94305-5103. Phone: 650-725-2910; Fax: 650-725-7085; E-mail: feldman{at}cmgm.stanford.edu.

Calcitriol exhibits antiproliferative and prodifferentiation effects in prostate cancer. Our goal is to further define the mechanisms underlying these actions. We studied established human prostate cancer cell lines and primary prostatic epithelial cells and showed that calcitriol regulated the expression of genes involved in the metabolism of prostaglandins (PGs), known stimulators of prostate cell growth. Calcitriol significantly repressed the mRNA and protein expression of prostaglandin endoperoxide synthase/cyclooxygenase-2 (COX-2), the key PG synthesis enzyme. Calcitriol also up-regulated the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme initiating PG catabolism. This dual action was associated with decreased prostaglandin E₂ secretion into the conditioned media of prostate cancer cells exposed to calcitriol. Calcitriol also repressed the mRNA expression of the PG receptors EP2 and FP, providing a potential additional mechanism of suppression of the biological activity of PGs. Calcitriol treatment attenuated PG-mediated functional responses, including the stimulation of prostate cancer cell growth. The combination of calcitriol with nonsteroidal anti-inflammatory drugs (NSAIDs) synergistically acted to achieve significant prostate cancer cell growth inhibition at 2 to 10 times lower concentrations of the drugs than when used alone. In conclusion, the regulation of PG metabolism and biological actions constitutes a novel pathway of calcitriol action that may contribute to its antiproliferative effects in prostate cells. We propose that a combination of calcitriol and nonselective NSAIDs might be a useful chemopreventive and/or therapeutic strategy in men with prostate cancer, as it would allow the use of lower concentrations of both drugs, thereby reducing their toxic side effects.

This article has been cited by other articles:

				S. SRINIVAS and D. FELDMAN A Phase II Trial of Calcitriol and Naproxen in Recurrent Prostate Cancer Anticancer Res, September 1, 2009; 29(9): 3605 - 3610. [Abstract] [Full Text] [PDF]

				M. THILL, S. BECKER, D. FISCHER, T. CORDES, A. HORNEMANN, K. DIEDRICH, D. SALEHIN, and M. FRIEDRICH Expression of Prostaglandin Metabolising Enzymes COX-2 and 15-PGDH and VDR in Human Granulosa Cells Anticancer Res, September 1, 2009; 29(9): 3611 - 3618. [Abstract] [Full Text] [PDF]

				M. THILL, D. FISCHER, S. BECKER, T. CORDES, C. DITTMER, K. DIEDRICH, D. SALEHIN, and M. FRIEDRICH Prostaglandin Metabolizing Enzymes in Correlation with Vitamin D Receptor in Benign and Malignant Breast Cell Lines Anticancer Res, September 1, 2009; 29(9): 3619 - 3625. [Abstract] [Full Text] [PDF]

				J. N. P. Rohan and N. L. Weigel 1{alpha},25-Dihydroxyvitamin D3 Reduces c-Myc Expression, Inhibiting Proliferation and Causing G1 Accumulation in C4-2 Prostate Cancer Cells Endocrinology, May 1, 2009; 150(5): 2046 - 2054. [Abstract] [Full Text] [PDF]

				Y. S. Kim, M. R. Young, G. Bobe, N. H. Colburn, and J. A. Milner Bioactive Food Components, Inflammatory Targets, and Cancer Prevention Cancer Prevention Research, March 1, 2009; 2(3): 200 - 208. [Abstract] [Full Text] [PDF]

				Y. Yin, J. Ni, M. Chen, Y. Guo, and S. Yeh RRR-{alpha}-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects Clin. Cancer Res., January 1, 2009; 15(1): 190 - 200. [Abstract] [Full Text] [PDF]

				Z. Liu, X. Wang, Y. Lu, S. Han, F. Zhang, H. Zhai, T. Lei, J. Liang, J. Wang, K. Wu, et al. Expression of 15-PGDH is downregulated by COX-2 in gastric cancer Carcinogenesis, June 1, 2008; 29(6): 1219 - 1227. [Abstract] [Full Text] [PDF]

				L. Nonn, D. Duong, and D. M. Peehl Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells Carcinogenesis, June 1, 2007; 28(6): 1188 - 1196. [Abstract] [Full Text] [PDF]

				S. Swami, A. V. Krishnan, J. Moreno, R. B. Bhattacharyya, D. M. Peehl, and D. Feldman Calcitriol and Genistein Actions to Inhibit the Prostaglandin Pathway: Potential Combination Therapy to Treat Prostate Cancer J. Nutr., January 1, 2007; 137(1): 205S - 210S. [Abstract] [Full Text] [PDF]