期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 68, 期 4, 页码 835-845出版社
SPRINGER
DOI: 10.1007/s00280-010-1552-1
关键词
Wogonin; GSK-3 beta; Delta Np63; Apoptosis
资金
- Chang Gung Memorial Hospital [CMRPD 180331]
Purpose Wogonin, a plant flavonoid, has antitumor activity in various cancers. Dysregulation of GSK-3 beta has been implicated in tumorigenesis and cancer progression. In this study, we investigated the antitumor activity and the mechanistic action of wogonin in human nasopharyngeal carcinoma (NPC) cells. Methods The effects of wogonin on the cell survival and apoptosis in NPC cells were investigated by MTS assay, flow cytometry, and PARP cleavage assays. Pharmacological inhibitors (BIO, LiCl, and OA), or small interfering RNA (siRNA) were used to address the expression status of GSK-3 beta and the anticancer effect of Delta Np63 in NPC cells. Results Wogonin was shown to induce dose-dependent cell apoptosis due to the induction of sub-G1-phase cells, PARP cleavage, and downregulation of Delta Np63, a survival factor in NPC cells. Strikingly, the apoptotic effect of wogonin involved GSK-3 beta inactivation via prominent inhibition of phosphorylation at Tyr216 and slightly increment of phosphorylation at Ser9, while there is no change in total GSK-3 beta proteins. Dysregulation of GSK-3 beta caused cell apoptosis was confirmed by pharmacological inhibitors (lithium chloroid, LiCl, and 6-bro-moindirubin3- oxime, BIO). Administration of okadaic acid (OA, a protein phosphatase inhibitor) that significantly inactivated GSK-3 beta also induced Delta Np63 downregulation and apoptosis. Targeted silencing of Delta Np63 repressed the phosphorylation of GSK-3 beta at Tyr216 and sensitized NPC cells to wogonin-induced apoptosis. Furthermore, GSK-3 beta or PP2A inhibitors enhanced wogonin-induced apoptosis via activation of caspase 3/7. Conclusion These results indicate that GSK-3 beta, as well as Delta Np63, are novel targets for wogonin action and suggest that wogonin might provide a potential therapeutic option in NPC. Further in vitro and in vivo studies will help to clarify the therapeutic role of wogonin in NPC.
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