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.