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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 (pErk1/2MAPK). Inhibition of pErk1/2MAPK 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–Erk1/2MAPK 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 Erk1/2MAPK-dependent modulation of constitutively active Stat3.
Footnotes
- Received March 19, 2015.
- Accepted July 1, 2015.
This work was supported by the National Institutes of Health/National Cancer Institute [Grant CA161931] and the University of Hawaii start-up funds. The Molecular and Cellular Immunology Core is supported in part by the National Institute of General Medical Sciences Centers of Biomedical Research Excellence [Grant P20-GM103516]. The Analytical Biochemistry Shared Resource is supported by the National Institutes of Health/National Cancer Institute P30 Cancer Center Support [Grant P30-CA71789].
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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