Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells

Abstract

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.

Thieny/Furanyl-hydroxyphenylpropenones as Inhibitors of LPS-induced ROS and NO Production in RAW 264.7 Macrophages, and Their Structure-Activity Relationship Study

“…Numerous polyphenolic phytochemicals such as resveratrol, curcumin, flavonoids, epigallocatechin gallate, and chalcones have been well studied and reported to interfere with specific stages of the carcinogenic process. [24][25][26][27] In our previous results, we observed that introduction of hydroxyl group on phenyl moiety increased bioa These authors contributed equally to this work. …”

Sinomenine induces apoptosis of prostate cancer cells by blocking activation of NF-kappa B

“…Similarly, in a recent study of fermented ginseng, another compound of Chinese medicine associated with anti-inflammatory effects, inhibition of NF-κB activity was detected (Yuan and Chung, 2010). Anti-tumor agents have also been shown to induce apoptosis by modulating NF-κB expression and activity (Pandey et al, 2007), Thus, strategies to inhibit NF-κB may provide a cancer therapy applicable to many types of carcinomas Zheng et al, 2007;Paule et al, 2007;Nonn et al, 2007). In this study, SN suppressed NF-κB activity and PGE2 production in a dose-dependent manner.…”

Department of ENT, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China

“…MKP-5 gene expression may be elevated as a negative feedback mechanism to counteract ERK activation. Importantly, data suggested that anti-inflammation activity by vitamin D and curcumin is mediated by MKP-5, which is a potential mechanism for prostate cancer prevention (20,21). In the mouse model of colon cancer, which was induced by azoxymethane and dextran sulfate sodium, ERK phosphorylation was significantly increased by about 10-fold (22).…”