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

• Type of Material: Article
• Authors: Jiansha Li, Huazhong University of Science and Technology; Mingyou Xing, Huazhong University of Science and Technology; Min Zhu, Huazhong University of Science and Technology; Xi Wang, Huazhong University of Science and Technology; Manxiang Wang, Huazhong University of Science and Technology; Sheng Zhou, Huazhong University of Science and Technology; Naping Li, Huazhong University of Science and Technology; Renliang Wu, Huazhong University of Science and Technology; Muxiang Zhou, Emory University
• Language: English
• Date: 2008-12-08
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Elsevier Ireland Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.canlet.2008.06.032
• Title of Journal or Parent Work: Cancer Letters
• ISSN: 0304-3835
• Volume: 272
• Issue: 1
• Start Page: 91
• End Page: 101
• Grant/Funding Information: This research was supported by a grant from the National Natural Science Foundation of China (No. 30470757 to RW), grants from the NIH (R01 CA123490 to MZ), the Leukemia and Lymphoma Society (6033-08 to MZ), CURE Childhood Cancer (to MZ)
• Keywords: Cancer; Survivin; GSK3β; Doxorubicin; Apoptosis
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

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.