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. 2009 May;329(2):524-31.
doi: 10.1124/jpet.108.148122. Epub 2009 Feb 2.

Glycogen synthase kinase-3beta mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia

Wei-Ching Huang  1 , Yee-Shin Lin, Chia-Ling Chen, Chi-Yun Wang, Wei-Hsin Chiu, Chiou-Feng Lin
Affiliations

Glycogen synthase kinase-3beta mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia

Wei-Ching Huang et al. J Pharmacol Exp Ther. 2009 May.

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.

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