Balance of NF-kappaB and p38 MAPK is a determinant of radiosensitivity of the AML-2 and its doxorubicin-resistant cell lines
| Autor: | Jisoo Yun, Sung-In Kang, Haidong Xu, Hyun Bark, Yoon-Kyeong Oh, Tae-Bum Lee, Cheol-Hee Choi |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Blotting Western Apoptosis Chromosomal translocation Radiation Tolerance p38 Mitogen-Activated Protein Kinases Granzymes Cell Line Tumor hemic and lymphatic diseases Radioresistance Humans RNA Messenger Radiosensitivity neoplasms Oligonucleotide Array Sequence Analysis bcl-2-Associated X Protein chemistry.chemical_classification Reactive oxygen species Antibiotics Antineoplastic biology Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling X-Rays Cytochrome c NF-kappa B Hydrogen Peroxide Hematology Oxidants Molecular biology Mitochondria Leukemia Myeloid Acute Protein Transport IκBα Proto-Oncogene Proteins c-bcl-2 Oncology chemistry Doxorubicin Drug Resistance Neoplasm Catalase biology.protein Reactive Oxygen Species Granzyme H |
| Zdroj: | Leukemia Research. 31:1267-1276 |
| ISSN: | 0145-2126 |
| DOI: | 10.1016/j.leukres.2006.11.006 |
| Popis: | This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100. |
| Databáze: | OpenAIRE |
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