title: A Resveratrol Analogue Promotes ERKMAPK-Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells.
abstract: (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 the most sensitive, with an IC50 of 6.7 μM, compared with normal fibroblasts, which have an IC50 > 20 μM. 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 extracellular signal-regulated kinase/mitogen-activated protein kinase 1/2 (pErk1/2(MAPK)). Inhibition of pErk1/2(MAPK) induction by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] blocked both the pserine727 Stat3 induction and ptyrosine705 Stat3 suppression by Cmpd1, indicating dependency on the mitogen-activated protein/extracellular signal-regulated kinase kinase-Erk1/2(MAPK) pathway for Cmpd1-induced modulation of Stat3 signaling. Cmpd1 also blocked epidermal growth factor-stimulated pStat1 induction, whereas upregulating pSrc, pAkt, p-p38, pHeat shock protein 27, and pmammalian target of rapamycin levels. However, pJanus kinase 2 and pEpidermal growth factor receptor levels were not significantly altered. Treatment of U251MG cells with Cmpd1 reduced in vitro colony formation, induced cell cycle arrest in the G2/M phase and cleavage of caspases 3, 8, and 9 and poly(ADP ribose) polymerase, and suppressed survivin, myeloid cell leukemia 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 Cmp1 occur in part by Erk1/2(MAPK)-dependent modulation of constitutively active Stat3.
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Chelsky
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Kondratyuk
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: David
authors.initials: D
authors.lastname: Paladino
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.).
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii (Z.L.C., P.Y., D.P., J.T.); Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (T.P.K., J.M.P.); and College of Pharmacy and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana (M.C.) jturkson@cc.hawaii.edu.
authors.forename: James
authors.initials: J
authors.lastname: Turkson
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: C000602001:4-(3,5-dimethoxystyryl)phenyl acetate; D000085:Acetates; D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D013267:Stilbenes; D014443:Tyrosine; D012694:Serine; D000077185:Resveratrol