Reactive oxygen species-regulated glycogen synthase kinase-3β activation contributes to all-trans retinoic acid-induced apoptosis in granulocyte-differentiated HL60 cells

Chi-Yun Wang, Tsan-Tzu Yang, Chia-Ling Chen, Wei-Chieh Lin, Chiou Feng Lin

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

All-trans retionic acid (ATRA) treatment confers disease remission in acute promyelocytic leukemia (APL) patients by inducing granulocytic differentiation, which is followed by cell apoptosis. Although glycogen synthase kinase (GSK)-3β is known to be required for spontaneous cell death in neutrophils, the requirement of GSK-3β activation for the apoptotic effects remains unknown. This question is addressed in the present study using a model of ATRA-induced granulocytic differentiation and apoptosis in APL HL60 cells. ATRA at a therapeutic concentration (1 μM) induced granulocytic differentiation, followed by apoptosis. ATRA treatment caused decreased Mcl-1, caspase-3 activation, and PARP cleavage following the inactivation of phosphatidylinositol 3-kinase/AKT and the activation of GSK-3β. Pharmacologically and genetically inhibiting GSK-3β effectively retarded ATRA-induced Mcl-1 degradation and apoptosis. Additional differentiation inducers, phorbol 12-myristate 13-acetate and dimethyl sulfoxide, also triggered GSK-3β-dependent apoptosis. Mechanistically, ATRA caused the generation of reactive oxygen species (ROS) through increased expression of NADPH oxidase subunits (p47phox and p67phox) to facilitate ATRA-induced GSK-3β activation and cell apoptosis. This study indicates that ROS initiate GSK-3β-dependent apoptosis in granulocyte-differentiated cells after long-term ATRA treatment.

Original languageEnglish
Pages (from-to)86-94
Number of pages9
JournalBiochemical Pharmacology
Volume88
Issue number1
DOIs
Publication statusPublished - Mar 1 2014

Keywords

  • Acute promyelocytic leukemia
  • All-trans retionic acid
  • Apoptosis
  • Glycogen synthase kinase-3β
  • NADPH oxidase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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