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.
Li
Jiansha
J
Department of Pathology, Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Xing
Mingyou
M
Zhu
Min
M
Wang
Xi
X
Wang
Manxiang
M
Zhou
Sheng
S
Li
Naping
N
Wu
Renliang
R
Zhou
Muxiang
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010957:Plasmids; D011485:Protein Binding; D000077022:Survivin; D014162:Transfection
D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D005231:Fatty Acids, Unsaturated; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C038753:leptomycin B