Abstract 5670: Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-κB activation and cyclooxygenase-2 expression in human breast epithelial cells: Cys179 of IKKβ as a potential target

Abstract

Abstract There are multiple lines of evidence supporting that inflammation is linked to carcinogenesis. Nuclear factor-κB (NF-κB), a master redox-sensitive transcription factor responsible for the induction of a wide array of proinflammatory genes, is frequently overactivated in many tumors. Moreover, constitutive activation of IκB kinase (IKK), a key regulator of NF-κB, has been implicated in inflammation-associated tumorigenesis. Piceatannol (3,5,3′4′-tetrahydroxy-trans-stilbene: PIC) derived from grapes, Rhubarb, and sugar cane, exhibits immunosuppressive and antitumorigenic activities in several cell lines, but the underlying mechanisms are poorly understood. In the present study, we found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetracecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-κB and cyclooxygenase-2 (COX-2) expression in MCF-10A cells. We hypothesize that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKβ, thereby inhibiting its catalytic activity. The reducing agent dithiothreitol and the antioxidant N-acetylcysteine abrogated inhibitory effects of PIC on TPA-induced activation of NF-κB and expression of COX-2. PIC incubated with whole cell lysate from MCF-10A cells stimulated with TPA inhibited IKKβ kinase activity. The inhibitory effect of PIC was reversed when DTT was cotreated. In addition, the inhibitory effects of PIC on NF-κB signaling and COX-2 induction were blunted in cells expressing mutant IKKβ (C179A) in which cysteine 179 was replaced by alanine. In conclusion, our results suggest that modification of cysteine residues of IKKβ by PIC blocks NF-κB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5670.