Inhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells.
In this study, the potential influence of resveratrol (3,5,4'-trihydroxy-trans-stilbene) in signal transducer and activator of transcription 3 (STAT3) signaling of medulloblastoma cells was evaluated by checking the status of STAT3 signaling and its downstream gene expression in two medulloblastoma cell lines (UW228-2 and UW228-3) with and without resveratrol treatment. The results revealed that resveratrol induced neuronal differentiation of medulloblastoma cells. Signal transducer and activator of transcription 3 expression and phosphorylation were detected in normally cultured UW228-2 and UW228-3 cells that were apparently attenuated after resveratrol treatment. The expression of STAT3 downstream genes, survivin, cyclin D1, Cox-2, and c-Myc, was suppressed but Bcl-2 was enhanced by resveratrol. Meanwhile, the production and secretion of leukemia inhibitory factor, a STAT3 activator, became active in resveratrol-treated cells. To further ascertain the significance of STAT3 signaling for medulloblastoma cells, AG490, a selective inhibitor of STAT3 phosphorylation, was used to treat UW228-3 cells. Phosphorylation of STAT3 was inhibited by AG490 accompanied with growth suppression, differentiation-like changes, and down-regulation of survivin, cyclin D1, Cox-2, and c-Myc. Our data thus suggest the importance of STAT3 signaling in maintenance and survival of medulloblastoma cells. This signaling may be the major target of resveratrol. Enhanced leukemia inhibitory factor and Bcl-2 expressions in resveratrol-treated cells might reflect a compensatory response to the loss of STAT3 function.
Yu
Li-Jun
LJ
Liaoning Laboratory of Cancer Genomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, 116044 Dalian, PR China.
Wu
Mo-Li
ML
Li
Hong
H
Chen
Xiao-Yan
XY
Wang
Qian
Q
Sun
Yuan
Y
Kong
Qing-You
QY
Liu
Jia
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; D013267:Stilbenes; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000077185:Resveratrol