A Resveratrol Analogue Promotes ERKMAPK-Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

被引:25
作者
Chelsky, Zachary L. [1 ]
Yue, Peibin [1 ]
Kondratyuk, Tamara P. [2 ]
Paladino, David [1 ]
Pezzuto, John M. [2 ]
Cushman, Mark [3 ,4 ]
Turkson, James [1 ]
机构
[1] Univ Hawaii, Ctr Canc, Nat Prod & Expt Therapeut Program, Honolulu, HI 96813 USA
[2] Univ Hawaii, Daniel K Inouye Coll Pharm, Hilo, HI 96720 USA
[3] Purdue Univ, Coll Pharm, W Lafayette, IN 47907 USA
[4] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA
基金
美国国家卫生研究院;
关键词
CHEMOPREVENTIVE AGENTS; MOLECULAR TARGETS; CANCER; ACTIVATION; TRANSCRIPTION; APOPTOSIS; PTEROSTILBENE; MECHANISMS; INHIBITOR; PROTEINS;
D O I
10.1124/mol.115.099093
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
(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 mu M. Notably, the human U251MG glioblastoma tumor line is the most sensitive, with an IC50 of 6.7 mu M, compared with normal fibroblasts, which have an IC50 > 20 mu M. 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.
引用
收藏
页码:524 / 533
页数:10
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