Glycogen synthase kinase 3β induces apoptosis in cancer cells through increase of survivin nuclear localization

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• 作者：Jiansha Li ; Mingyou Xing ; Min Zhu ; Xi Wang ; Manxiang Wang ; Sheng Zhou ; Naping Li ; Renliang Wu ; Muxiang Zhou
• 关键词：GSK3β ; Survivin ; Cancer ; Doxorubicin ; Apoptosis
• 刊名：Cancer Letters
• 出版年：2008
• 出版时间：8 December 2008
• 年：2008
• 卷：272
• 期：1
• 页码：91-101
• 全文大小：518 K

文摘

Glycogen synthase kinase 3β (GSK3β) regulates numerous signaling pathways that control a wide range of cellular processes, including cell proliferation, differentiation, apoptosis and metabolism. We report a novel function of GSK3β: It interacts with the inhibitor-of-apoptosis protein (IAP) survivin to modulate its expression, thus regulating apoptosis in human lung cancer cells. A co-immunoprecipitation assay revealed that GSK3β can bind survivin. Activation of GSK3β induced translocation of survivin from the cytoplasm to the nucleus, resulting in G1 cell-cycle arrest and apoptosis, as well as sensitization to the chemotherapeutic drug doxorubicin. In contrast, inactivation of GSK3β, either by transfection of a dominant-negative mutant inhibitor DN-GSK3β or with selective inhibitor LiCl, increased cytoplasmic survivin expression, leading to cell-cycle progression and resistance to apoptosis. These results identify a pro-apoptotic role for GSK3β in cancer cells, through its modulation of survivin in subcellular redistribution. This new role suggests that there is a potential for pharmacologic activation of GSK3β to enhance treatment of cancer patients, including those with resistance.