TY - JOUR
T1 - Reactive oxygen species-regulated glycogen synthase kinase-3β activation contributes to all-trans retinoic acid-induced apoptosis in granulocyte-differentiated HL60 cells
AU - Wang, Chi Yun
AU - Yang, Tsan Tzu
AU - Chen, Chia Ling
AU - Lin, Wei Chieh
AU - Lin, Chiou Feng
N1 - Funding Information:
We thank the Immunobiology Core, Research Center of Clinical Medicine, National Cheng Kung University Hospital for providing services, including training, technical support, and assistance with the experimental design and data analysis using the Flow Cytometry Core facilities. This work was supported by grant NSC 100-2320-B-006-009-MY3 from the National Science Council, Taiwan .
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bcp.2013.12.021
DO - 10.1016/j.bcp.2013.12.021
M3 - Article
C2 - 24406248
AN - SCOPUS:84896707473
SN - 0006-2952
VL - 88
SP - 86
EP - 94
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 1
ER -