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

Glycogen synthase kinase 3beta (GSK3beta) 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 GSK3beta: 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 GSK3beta can bind survivin. Activation of GSK3beta 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 GSK3beta, either by transfection of a dominant-negative mutant inhibitor DN-GSK3beta 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 GSK3beta in cancer cells, through its modulation of survivin in subcellular redistribution. This new role suggests that there is a potential for pharmacologic activation of GSK3beta to enhance treatment of cancer patients, including those with resistance.