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The role of p38 MAPK and JNK in Arsenic trioxide‐induced mitochondrial cell death in human cervical cancer cells
Author(s) -
Kang YoungHee,
Lee SuJae
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21470
Subject(s) - p38 mitogen activated protein kinases , microbiology and biotechnology , apoptosis , mapk/erk pathway , programmed cell death , phosphorylation , mitochondrion , hela , kinase , inner mitochondrial membrane , arsenic trioxide , chemistry , reactive oxygen species , biology , cell , biochemistry
Previously, we have shown that the release of AIF from mitochondria is required for As 2 O 3 ‐induced cell death in human cervical cancer cells, and that reactive oxygen species (ROS) is necessary for AIF release from mitochondria. In this study, we further investigated the role of MAPKs in ROS‐mediated mitochondrial apoptotic cell death triggered by As 2 O 3 . As 2 O 3 ‐induced apoptotic cell death in HeLa cells was associated with activation and mitochondrial translocation of Bax, a marked phosphorylation of Bcl‐2, reduction of Bcl‐2 and Bax interaction, dissipation of mitochondrial membrane potential. Using small interfering RNA, reduced Bax expression effectively attenuated As 2 O 3 ‐induced mitochondrial membrane potential loss and apoptotic cell death. Moreover, the phosphorylation of Bcl‐2 induced by As 2 O 3 diminished its ability to bind to Bax. Treatment of cells with As 2 O 3 activated both the p38 MAPK and JNK pathways. Mitochondrial translocation of Bax was completely suppressed in the presence of p38 MAPK inhibitor PD169316 or si‐p38 MAPK. The As 2 O 3 ‐induced Bcl‐2 phosphorylation was attenuated largely by JNK inhibition using SP600125 or si‐JNK and to some extent by p38 MAPK inhibition with PD169316 or si‐p38 MAPK. In addition, N ‐acetyl‐ L ‐cystein (NAC), a thiol‐containing anti‐oxidant, completely blocked As 2 O 3 ‐induced p38 MAPK and JNK activations, mitochondria translocation of Bax, and phosphorylation of Bcl‐2. These results support a notion that ROS‐mediated activations of p38 MAPK and JNK in response to As 2 O 3 treatment signals activation of Bax and phosphorylation of Bcl‐2, resulting in mitochondrial apoptotic cell death in human cervical cancer cells. J. Cell. Physiol. 217: 23–33, 2008. © 2008 Wiley‐Liss, Inc.