Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-{kappa}B activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKK{beta} as a potential target.
There are multiple lines of evidence supporting that chronic inflammation is linked to carcinogenesis. Nuclear factor-kappaB (NF-kappaB), a major redox-sensitive transcription factor responsible for the induction of a wide array of pro-inflammatory genes, is frequently overactivated in many tumors. Moreover, constitutive activation of IkappaB kinase (IKK), a key regulator of NF-kappaB signaling, has been implicated in inflammation-associated tumorigenesis. Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene; PIC) derived from grapes, rhubarb and sugarcane 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-tetradecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-kappaB and expression of cyclooxygenase-2 (COX-2) in MCF-10A cells. We speculate that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKbeta, thereby inhibiting its catalytic activity. In support of this speculation, the reducing agent dithiothreitol abrogated the inhibitory effects of PIC on TPA-induced activation of NF-kappaB signaling and expression of COX-2. In addition, the inhibitory effects of PIC on NF-kappaB activation and COX-2 induction were blunted in cells expressing mutant IKKbeta (C179A) in which cysteine 179 was replaced by alanine. In conclusion, our results show that direct modification of IKKbeta by PIC, presumably at the cysteine 179 residue, blocks NF-kappaB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells.
Son
Pil-Soon
PS
Cancer Research Institute, Seoul National University, South Korea.
Park
Sin-Aye
SA
Na
Hye-Kyung
HK
Jue
Dae-Myung
DM
Kim
Sanghee
S
Surh
Young-Joon
YJ
D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D001940:Breast / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D003545:Cysteine / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology*; D010636:Phenols / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D059808:Polyphenols; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects
D016588:Anticarcinogenic Agents; D005419:Flavonoids; D016328:NF-kappa B; D010636:Phenols; D010703:Phorbol Esters; D059808:Polyphenols; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D003545:Cysteine; D000077185:Resveratrol