Role of p38 MAPK and JNK in enhanced cervical cancer cell killing by the combination of arsenic trioxide and ionizing radiation.
Enhancement of radiation response is possible to be achieved by combination treatment with therapeutic drugs. Previously we have shown that As2O3 in combination with ionizing radiation enhanced radiation response in cervical cancer cells. In this study, we further investigated molecular mechanism of synergistic enhancement of radiation response in combination with As2O3. The combination treatment of HeLa cells induced translocation of Bax to the mitochondria and a marked phosphorylation of Bcl-2. p38 MAPK and JNK were also found to be activated in response to the combination treatment. Pretreatment of PD169316, a p38 MAPK specific inhibitor, completely attenuated the combination treatment-induced mitochondrial relocalization of Bax, and altered Bcl-2 phosphorylation. Moreover, pretreatment of SP600125, JNK specific inhibitor, clearly attenuated Bcl-2 phosphorylation, but did not affect Bax translocation to the mitochondria. In addition, N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, completely blocked p38 MAPK and JNK activations, Bax relocalization and Bcl-2 phosphorylation. These results indicate that activation of p38 MAPK is specifically required for translocation of Bax to the mitochondria, and both JNK and p38 MAPK are involved in phosphorylation of Bcl-2 in response to combination treatment with gamma-radiation and As2O3, and that ROS is a critical regulator of p38 MAPK and JNK activations. The molecular mechanism elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to radiation treatment.
Kang
Young-Hee
YH
Laboratory of Molecular Biochemistry, Department of Chemistry, Hanyang University, Seoul, Korea.
Lee
Su-Jae
SJ
D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003131:Combined Modality Therapy; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010087:Oxides / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001152:Arsenicals; D010087:Oxides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D020169:Caspases; D000077237:Arsenic Trioxide