Phorbol Ester Induction Piceatannol Mcf-10a Of Nf-¦Êb Activation And Cox-2 Expression Inhibition

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis.Abnormal upregulation of cyclooxygenase-2(COX-2),a rate-limiting enzyme in the prostaglandin biosynthesis,has been implicated in carcinogenesis.Previously,it has been reported that resveratrol(trans-3,4',5-trihydroxystilbene)suppresses the activation of the nuclear transcription factor NF-κB,one of the major transcription factors that regulate cox-2 gene transcription.Piceatannol,(trans-3,4,3',5'-tetrahydroxystilbene)primarily derived from the seeds of Euphorbia lagascae,exhibits potent anti-inflammatory and anti-proliferative activities,but the underlying molecular mechanisms remain largely unresolved.In the present study,we examined whether piceatannol,structurally analogous to resveratrol,could also suppress both COX-2 expression and NF-κB activation.Piceatannol abrogated the expression of 12-O-teradecanoylphorbol-13-acetate(TPA)-induced expression of COX-2 and its mRNA transcript in human mammary epithelial(MCF-10A)cells.The treatment of MCF-10A cells with piceatannol suppressed TPA-induced NF-κB DNA binding activity to a greater extent than did resveratrol and another stilbene analog oxyresveratrol(trans-2,3',4,5'-tetrahydroxystilbene), indicative of the critical role of the orientation as well as the number of hydroxyl groups in its NF-κB inhibitoty activity.Piceatannol also inhibited TPA-induced phosphorylation and degradation of IκBαas well as nuclear translocation of p65.The thiol reducing agent dithiothreitol(DTT)abrogated the inhibitory effects of piceatannol on NF-κB DNA binding, presumably by keeping the cysteine residues in the kinase domain of IKKβin a reduced state.The possibility of direct inhibition of NF-κB transcriptional activity by piceatannol is under investigation.