INHIBITION OF THE C-JUN N-TERMINAL KINASE (JNK) SIGNALING PATHWAY BY CURCUMIN

Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-k appa B activation. In this report, we show that curcumin inhibits JNK activation by various agonists including PMA plus ionomycin, anisomyci n, UV-C, gamma radiation, TNF-alpha, and sodium orthovanadate. Althoug h both JNK and ERK activation by phorbol 12-myristate 13-acetate (PMA) plus ionomycin were suppressed by curcumin, the JNK pathway was more sensitive. The IC50 (50% inhibition concentration) of curcumin was bet ween 5-10 mu M for JNK activation and was 20 mu M for ERK activation. Tn transfection assays, curcumin moderately suppressed MEKK1-induced J NK activation; however, it effectively blocked JNK activation caused b y co-transfection of TAK1, CCK, or HPK1. Curcumin did not directly inh ibit JNK, SEK1, MEKK1 or HPK1 activity. Although cnrcumin suppressed T AK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo. Our data sug gest that curcumin may affect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPKKK level. Taken together, the inhibition of the MEKK1-JNK pathway reveals a possible mechanism of suppression of AP-1 and NF-kappa B sig naling by curcumin, and may explain the potent anti-inflammatory and a nti-carcinogenic effects of this chemical.