Carcinogenesis Advance Access originally published online on December 6, 2006
Carcinogenesis 2007 28(6):1188-1196; doi:10.1093/carcin/bgl241
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Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells
Department of Urology, Stanford University, Stanford, CA 94305-5118, USA
* To whom correspondence should be addressed. Tel: +1 650 725 5531; Fax: +1 650 723 4200; Email: dpeehl{at}stanford.edu
As inflammation emerges as a risk factor for prostate cancer (PCa), there is potential for chemoprevention by anti-inflammatory agents. Dietary phytochemicals have been shown to have chemopreventive properties which may include anti-inflammatory activities. In this study, we demonstrate a role for mitogen-activated protein kinase phosphatase-5 (MKP5) in mediating anti-inflammatory activities of the phytochemicals curcumin, resveratrol and [6]-gingerol. We utilized the cytokines tumor necrosis factor-
(TNF) and interleukin (IL)-1ß to increase p38-dependent nuclear factor kappa-B (NF
B) activation and expression of pro-inflammatory genes cyclooxygenase-2 (COX-2), IL-6 and IL-8 in normal prostatic epithelial cells. MKP5 over-expression decreased cytokine-induced NFB activation, COX-2, IL-6 and IL-8 in normal prostatic epithelial cells, suggesting potent anti-inflammatory activity of MKP5. Pretreatment of cells with a p38 inhibitor mimicked the results observed with MKP5 over-expression, further implicating p38 inhibition as the main activity of MKP5. Curcumin, the phytochemical found in turmeric, up-regulated MKP5, subsequently decreasing cytokine-induced p38-dependent pro-inflammatory changes in normal prostatic epithelial cells. Resveratrol and [6]-gingerol, phytochemicals present in red wine and ginger, respectively, also up-regulated MKP5 in normal prostate epithelial cells. Moreover, we found that PCa cell lines DU 145, PC-3, LNCaP and LAPC-4 retained the ability to up-regulate MKP5 following curcumin, resveratrol and [6]-gingerol exposure, suggesting utility of these phytochemicals in PCa treatment. In summary, our findings show direct anti-inflammatory activity of MKP5 in prostate cells and suggest that up-regulation of MKP5 by phytochemicals may contribute to their chemopreventive actions by decreasing prostatic inflammation.
Abbreviations: COX-2, cyclooxygenase-2; 1,25D1, 25-dihydroxyvitamin D3; DMSO, dimethyl sulfoxide; E-PZ, epithelial cells derived from the normal peripheral zone; IL, interleukin; JNK, jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKP5, mitogen-activated protein kinase phosphatase 5; mRNA, messenger RNA; NFB, nuclear factor kappa B; Pca, prostate cancer; siRNA, small interference RNA; TNF, tumor necrosis factor ; VDR, vitamin D receptor; T +I, TNF and IL-1ß
Received August 2, 2006; revised August 31, 2006; accepted November 27, 2006.
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