Glycogen Synthase Kinase-3 Mediates Endoplasmic Reticulum Stress-Induced Lysosomal Apoptosis in Leukemia

Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2009; 329(2):524-31. DOI: 10.1124/jpet.108.148122
Source: PubMed


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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    • "Recent studies [101,102] reported that inhibiting glycogen synthase kinase (GSK)-3, a multi-functional serine/threonine kinase that controls protein synthesis, cell proliferation, division, differentiation, motility, inflammation, and apoptosis, downregulates Toll-like receptor (TLR)-mediated inflammatory responses but increases IL-10 production. We recently showed that GSK-3 regulates inflammatory activation in lipopolysaccharide (LPS)-activated macrophages, partly through inhibiting IL-10 [103]. Mechanistically, GSK-3 negatively regulates CREB, a transcription factor that promotes IL-10 [101,102,104]. "
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    • "Often, such secondary LMP is initiated by caspase-9, which can be activated in the apoptososome or, in murine cells, by caspase-8-dependent cleavage (Gyrd- Hansen et al., 2006; Oberle et al., 2010). Furthermore, caspase-2 has been reported to cause LMP and subsequent activation of other caspases in tunicamycin-treated leukemia cells (Huang et al., 2009). The caspase targets that are responsible for LMP remain mostly speculative (Oberle et al., 2010). "
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    • "Previously, UPR has shown that GSK3β is involved in the cytosolic localization of p53 during ER stress, which prevents p53-dependent apoptosis during early ER stress [26], [30]. In addition to p53, GSK3β regulates the activation of caspase-2 during ER stress in leukemia [38]. GSK3β is required for the induction of long-chain acyl-CoA synthetase 3 (ACSL3) and lipid accumulation in response to ER stress [39]. "
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