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J Biol Chem. 2013 May 10;288(19):13269-77. doi: 10.1074/jbc.M112.402560. Epub 2013 Mar 27.

The Arf/p53 protein module, which induces apoptosis, down-regulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs.

Author information

1
Division of Genome Stability Research, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Abstract

BACKGROUND:

It is unclear how DNA-damaging agents target cancer cells over normal somatic cells.

RESULTS:

Arf/p53-dependent down-regulation of H2AX enables normal cells to survive after DNA damage.

CONCLUSION:

Transformed cells, which harbor mutations in either Arf or p53, are more sensitive to DNA-damaging agents.

SIGNIFICANCE:

Cellular transformation renders cells more susceptible to some DNA-damaging agents. 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 γH2AX (phosphorylated form of H2AX at Ser-139) is a critical factor that determines drug sensitivity and should be considered when administering chemotherapy.

KEYWORDS:

ARF; Arf/p53 Module; Camptothecin; Cancer Chemotherapy; Cancer Therapy; Cell Biology; DNA Damage Response; H2AX; p53; γH2AX

PMID:
23536184
PMCID:
PMC3650366
DOI:
10.1074/jbc.M112.402560
[Indexed for MEDLINE]
Free PMC Article

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