期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 19, 页码 13269-13277出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.402560
关键词
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资金
- National Cancer Center Research and Development Fund [23-C-10]
- MEXT KAKENHI [20770136]
- Foundation for Promotion of Cancer Research
- Grants-in-Aid for Scientific Research [23501271, 23616003, 13J10618, 25860245] Funding Source: KAKEN
Anti-cancer drugs generally target cancer cells rather than normal somatic cells. However, the factors that determine this differential sensitivity are poorly understood. Here we show that Arf/p53-dependent down-regulation of H2AX induced the selective survival of normal cells after drug treatment, resulting in the preferential targeting of cancer cells. Treatment with camptothecin, a topoisomerase I inhibitor, caused normal cells to down-regulate H2AX and become quiescent, a process mediated by both Arf and p53. In contrast, transformed cells that harbor mutations in either Arf or p53 do not down-regulate H2AX and are more sensitive to drugs unless they have developed drug resistance. Such transformation-associated changes in H2AX expression rendered cancer cells more susceptible to drug-induced damage (by two orders of magnitude). Thus, the expression of H2AX and gamma H2AX (phosphorylated form of H2AX at Ser-139) is a critical factor that determines drug sensitivity and should be considered when administering chemotherapy.
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