Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells.
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-alpha (TNFalpha) and interleukin (IL)-1beta to increase p38-dependent nuclear factor kappa-B (NFkappaB) 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 NFkappaB 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.
Nonn
Larisa
L
Department of Urology, Stanford University, Stanford, CA 94305-5118, USA.
Duong
David
D
Peehl
Donna M
DM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D054637:Dual-Specificity Phosphatases; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008517:Phytotherapy; D011467:Prostate / Q000166:cytology / Q000201:enzymology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases; D054637:Dual-Specificity Phosphatases; D003474:Curcumin