title: Glycogen synthase kinase-3 (GSK-3) inhibition induces apoptosis in leukemic cells through mitochondria-dependent pathway.
abstract: The roles of glycogen synthase kinase-3 (GSK-3) in cell survival and apoptosis are controversial. We examined the effect of a specific GSK-3 inhibitor (SB-415286) on the regulation of leukemic cells proliferation and apoptosis. SB-415286 (40 μM) induced cell growth inhibition, β-catenin stabilization, cell cycle arrest in G(2)/M phase, cyclin B1 downregulation, and apoptosis in leukemic cell lines KG1a, K562, and CMK. Blocking the death receptor pathway by using a specific inhibitor of caspase-8, did not inhibit SB-415286-induced apoptosis. This indicates that activation of caspase-8 is part of the intrinsic apoptotic pathway and occurs downstream of mitochondria membrane potential depolarization mediated by other caspases. Furthermore, we found that depolarization of mitochondria membrane caused by GSK-3 inhibition is regulated by dephosphorylation of anti-apoptotic protein Bcl-2 and downregulation of Bcl-xL. Thus, inhibition of GSK-3-induced apoptosis of leukemic cells could be an attractive target for treatment of leukemia.
authors.affiliation: Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway. reza@medisin.uio.no
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Mirlashari
authors.forename: Ingrid
authors.initials: I
authors.lastname: Randen
authors.forename: Jens
authors.initials: J
authors.lastname: Kjeldsen-Kragh
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D046529:Microscopy, Electron, Transmission
chemical_list: D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3