Glycogen Synthase Kinase-3 Mediates Endoplasmic Reticulum Stress-Induced Lysosomal Apoptosis in Leukemia
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.
Available from: Chiou-Feng Lin
- "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 . Mechanistically, GSK-3 negatively regulates CREB, a transcription factor that promotes IL-10 [101,102,104]. "
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ABSTRACT: Infection with dengue virus (DENV) causes both mild dengue fever and severe dengue diseases, such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms for DENV are complicated, involving viral cytotoxicity, immunopathogenesis, autoimmunity, and underlying host diseases. Viral load correlates with disease severity, while the antibody-dependent enhancement of infection largely determines the secondary effects of DENV infection. Epidemiological and experimental studies have revealed an association between the plasma levels of interleukin (IL)-10, which is the master anti-inflammatory cytokine, and disease severity in patients with DENV infection. Based on current knowledge of IL-10-mediated immune regulation during infection, researchers speculate an emerging role for IL-10 in clinical disease prognosis and dengue pathogenesis. However, the regulation of dengue pathogenesis has not been fully elucidated. This review article discusses the regulation and implications of IL-10 in DENV infection. For future strategies against DENV infection, manipulating IL-10 may be an effective antiviral treatment in addition to the development of a safe dengue vaccine.
Journal of Biomedical Science 06/2013; 20(1):40. DOI:10.1186/1423-0127-20-40 · 2.76 Impact Factor
Available from: Marja Jaattela
- "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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ABSTRACT: Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called "lysosomal cell death". This form of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream mechanisms that lead to lysosomal membrane permeabilization.
Journal of Cell Science 05/2013; 126(Pt 9):1905-1912. DOI:10.1242/jcs.091181 · 5.43 Impact Factor
Available from: Jui-Hsiang Hung
- "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 , . In addition to p53, GSK3β regulates the activation of caspase-2 during ER stress in leukemia . GSK3β is required for the induction of long-chain acyl-CoA synthetase 3 (ACSL3) and lipid accumulation in response to ER stress . "
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ABSTRACT: Induction of apoptosis by endoplasmic reticulum (ER) stress is implicated as the major factor in the development of multiple diseases. ER stress also appears to be a potentially useful major response to many chemotherapeutic drugs and environmental chemical compounds. A previous study has indicated that one major apoptotic regulator, p53, is significantly increased in response to ER stress, and participates in ER stress-induced apoptosis. However, the regulators of p53 expression during ER stress are still not fully understood.
In this report, we demonstrate that induction of p53 expression is mediated through NF-κB signaling pathways during ER stress in MCF-7 cells. Tunicamycin or brefeldin A, two ER stress inducers, increased p53 expression in MCF-7 and Hela cells. We found p53 nuclear localization, activity, and phosphorylation at serine 15 on p53 increased during ER stress. Nuclear translocation of NF-κB and activity of NF-κB were also observed during ER stress. ER stress-induced p53 expression was significantly inhibited by coincubation with the NF-κB inhibitor, Bay 11-7082 and downregulation of NF-κB p65 expression. The role of p53 in mediating Brefeldin A-induced apoptosis was also investigated. Induction of p53 expression by Brefeldin A was correlated to Brefeldin A-induced apoptosis. Furthermore, downregulation of p53 expression by p53 siRNA significantly reduced Brefeldin A-induced apoptosis in MCF-7 cells.
Taken together, NF-κB activation and induction of p53 expression is essential for ER stress-induced cell death which is important for therapeutic effects of clinical cancer drugs. Our results may provide insight into the mechanism of cancer chemotherapy efficacy that is associated with induction of ER stress.
PLoS ONE 07/2012; 7(7):e39120. DOI:10.1371/journal.pone.0039120 · 3.23 Impact Factor
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