title: Glycogen synthase kinase-3beta mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia.
abstract: Glycogen synthase kinase (GSK)-3beta may modulate endoplasmic reticulum (ER) stress-induced apoptosis; however, the mechanism remains unclear. Our data showed that human monocytic leukemia/lymphoma U937 and acute myeloid leukemia HL-60, but not chronic myeloid leukemia K562, cells were susceptible to apoptosis induced by ER stressor tunicamycin, a protein glycosylation inhibitor. Tunicamycin caused early activation of caspase-2, -3, -4, and -8, followed by apoptosis, whereas caspase-9 was slowly activated. Inhibiting caspase-2 reduced activation of caspase-8 and -3 but had no effect on caspase-4. Tunicamycin induced apoptosis independently of the mitochondrial pathway but caused lysosomal destabilization followed by lysosomal membrane permeabilization (LMP), cathepsin B relocation from lysosomes to the cytosol, and caspase-8 and -3 activation. It is notable that caspase-2 mediated lysosomal destabilization. Inhibiting GSK-3beta comprehensively reduced lysosomal apoptosis after caspase-2 inhibition. Unlike U937 and HL-60 cells, K562 cells showed nonresponsive ER stress and failure of activation of GSK-3beta and caspase-2 in response to tunicamycin. Activating GSK-3beta caused K562 cells to be susceptible to tunicamycin-induced apoptosis. Taken together, we show that GSK-3beta exhibits a mechanism of ER stress-induced lysosomal apoptosis in leukemia involving caspase-2-induced LMP and cathepsin B relocation, which result in caspase-8 and -3 activation.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Chi-Yun
authors.initials: CY
authors.lastname: Wang
authors.forename: Wei-Hsin
authors.initials: WH
authors.lastname: Chiu
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006031:Glycosylation; D018922:HL-60 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D020014:K562 Cells; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability; D014415:Tunicamycin / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D014415:Tunicamycin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020169:Caspases