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

Glycogen synthase kinase 30 (GSK3 beta) 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 GSK3 beta: 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 GSK3 beta can bind survivin. Activation of GSK3 beta 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 GSK3 beta, either by transfection of a dominant-negative mutant inhibitor DN-GSK3 beta 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 GSK3 beta in cancer cells, through its modulation of survivin in subcellular redistribution. This new role suggests that there is a potential for pharmacologic activation of GSK3 beta to enhance treatment of cancer patients, including those with resistance. (C) 2008 Elsevier Ireland Ltd. All rights reserved.