The role of p38 MAPK and JNK in Arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells.

Abstract

Previously, we have shown that the release of AIF from mitochondria is required for As2O3-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 As2O3. As2O3-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 As2O3-induced mitochondrial membrane potential loss and apoptotic cell death. Moreover, the phosphorylation of Bcl-2 induced by As2O3 diminished its ability to bind to Bax. Treatment of cells with As2O3 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 As2O3-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 As2O3-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 As2O3 treatment signals activation of Bax and phosphorylation of Bcl-2, resulting in mitochondrial apoptotic cell death in human cervical cancer cells.

• Authors: Young-Hee Kang, Su-Jae Lee
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 217 Issue 1 Pg. 23-33 (Oct 2008) ISSN: 1097-4652 [Electronic] United States
• PMID: 18412143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Arsenicals
• Oxides
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Arsenic Trioxide

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Blotting, Western
• Enzyme Activation (drug effects)
• Female
• HeLa Cells
• Humans
• MAP Kinase Kinase 4 (drug effects, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects)
• Oxides (pharmacology)
• Phosphorylation
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• RNA, Small Interfering
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects, physiology)
• Transfection
• Uterine Cervical Neoplasms (drug therapy)
• bcl-2-Associated X Protein (drug effects, metabolism)
• p38 Mitogen-Activated Protein Kinases (drug effects, metabolism)