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

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

Research output: Contribution to journalArticle

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Abstract

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 tunicamy-cin-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.

Original languageEnglish
Pages (from-to)524-531
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number2
DOIs
Publication statusPublished - May 2009

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Glycogen Synthase Kinase 3
Caspase 2
Endoplasmic Reticulum Stress
Leukemia
Tunicamycin
Apoptosis
Caspase 3
K562 Cells
Caspase 8
Cathepsin B
Membranes
Caspase 9
HL-60 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Caspases
Lysosomes
Glycosylation
Acute Myeloid Leukemia
Endoplasmic Reticulum
Cytosol

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Glycogen synthase kinase-3β mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia. / Huang, Wei-Ching; Lin, Yee-Shin; Chen, Chia-Ling; Wang, Chi-Yun; Chiu, Wei-Hsin; Lin, Chiou Feng.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 329, No. 2, 05.2009, p. 524-531.

Research output: Contribution to journalArticle

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