TY - JOUR T1 - A Resveratrol Analogue Promotes ERKMAPK-Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro Against Human Tumor Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.099093 SP - mol.115.099093 AU - Zachary L Chelsky AU - Peibin Yue AU - Tamara P Kondratyuk AU - David Paladino AU - John M Pezzuto AU - Mark Cushman AU - James Turkson Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/07/02/mol.115.099093.abstract N2 - (E)-4-(3,5-Dimethoxystyryl)phenyl acetate (Cmpd1) is a resveratrol analog that preferentially inhibits glioma, breast and pancreatic cancer cell growth, with IC50 values of 6-19 μM. Notably, the human U251MG glioblastoma tumor line is most sensitive, with an IC50 of 6.7 μM, compared to normal fibroblasts, with IC50 >20 μM. Immunoblotting analysis shows treatment of U251MG cells that harbor aberrantly-active Signal Transducer and Activator of Transcription (Stat)3 with Cmpd1 suppresses Stat3 tyrosine705 phosphorylation in a dose-dependent manner, in parallel with the induction of pserine727 Stat3 and pErk1/2MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase 1/2). Inhibition of pErk1/2MAPK induction by the MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) inhibitor, PD98059, blocked both the pserine727 Stat3 induction and ptyrosine705 Stat3 suppression by Cmpd1, indicating the dependency on the MEK-Erk1/2MAPK pathway for Cmpd1-induced modulation of Stat3 signaling. Cmpd1 also blocked epidermal growth factor (EGF)-stimulated pStat1 induction, while upregulating pSrc, pAkt, p-p38, pHsp (heat shock protein)27, and pmTOR (mammalian target of rapamycin) levels. However, pJanus kinase (Jak)2 and pEGFR (EGF receptor) levels were not significantly altered. Treatment of U251MG cells with Cmpd1 reduced in vitro colony formation, induced cell cycle arrest in G2/M phase and the cleavage of caspases 3, 8 and 9 and poly ADP ribose polymerase (PARP), and suppressed Survivin, Mcl-1, Bcl-xL, Cyclin D1, and Cyclin B1 expression. Taken together, these data identify a novel mechanism for the inhibition of Stat3 signaling by a resveratrol analog and suggest that the preferential growth inhibitory effects of Cmpd1 occur in part by Erk1/2MAPK-dependent modulation of constitutively-active Stat3. ER -