TY - JOUR T1 - Glycogen Synthase Kinase-3β Mediates Endoplasmic Reticulum Stress-Induced Lysosomal Apoptosis in Leukemia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 524 LP - 531 DO - 10.1124/jpet.108.148122 VL - 329 IS - 2 AU - Wei-Ching Huang AU - Yee-Shin Lin AU - Chia-Ling Chen AU - Chi-Yun Wang AU - Wei-Hsin Chiu AU - Chiou-Feng Lin Y1 - 2009/05/01 UR - http://jpet.aspetjournals.org/content/329/2/524.abstract N2 - Glycogen synthase kinase (GSK)-3β 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-3β 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-3β and caspase-2 in response to tunicamycin. Activating GSK-3β caused K562 cells to be susceptible to tunicamycin-induced apoptosis. Taken together, we show that GSK-3β 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. The American Society for Pharmacology and Experimental Therapeutics ER -