This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Nonn, L. Articles by Peehl, D. M. Search for Related Content PubMed PubMed Citation Articles by Nonn, L. Articles by Peehl, D. M. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

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

Requests for reprints: Donna M. Peehl, Department of Urology, Stanford Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5118. Phone: 650-725-5531; Fax: 650-723-4200; E-mail: dpeehl{at}stanford.edu.

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D₃ (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor –stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D. (Cancer Res 2006; 66(8): 4516-24)

This article has been cited by other articles:

				T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]

				Y. Xu, F. Fang, D. K. St. Clair, S. Josson, P. Sompol, I. Spasojevic, and W. H. St. Clair Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1{alpha},25-dihydroxyvitamin D3 in prostate cancer cells Mol. Cancer Ther., July 1, 2007; 6(7): 2048 - 2056. [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]

				A. G. Papatsoris, M. V. Karamouzis, and A. G. Papavassiliou The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics Mol. Cancer Ther., March 1, 2007; 6(3): 811 - 819. [Abstract] [Full Text] [PDF]