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Oxidative stress induces a prolonged but reversible arrest in p53-null cancer cells, involving a Chk1-dependent G2 checkpoint

Abstract

Reactive oxygen species (ROS), the principal mediators of oxidative stress, induce responses such as apoptosis or permanent growth arrest/senescence in normal cells. Moreover, p53 activation itself contributes to ROS accumulation. Here we show that treatment of p53-null cancer cells with sublethal concentrations of ROS triggered an arrest with some morphological similarities to cellular senescence. Different from a classical senescent arrest in G1, the ROS-induced arrest was predominantly in the G2 phase of the cell cycle, and its establishment depended at least in part on an intact Chk1-dependent checkpoint. Chk1 remained phosphorylated only during the repair of double strand DNA breaks, after which Chk1 was inactivated, the G2 arrest was suppressed, and some cells recovered their ability to proliferate. Inhibition of Chk1 by an RNAi approach resulted in an increase in cell death in p53-null cells, showing that the Chk1-dependent G2 checkpoint protected cells that lacked a functional p53 pathway from oxidative stress. It has been proposed that the induction of a senescent-like phenotype by antineoplastic agents can contribute therapeutic efficacy. Our results indicate that oxidative stress-induced growth arrest of p53-null tumor cells cannot be equated with effective therapy owing to its reversibility and supports the concept that targeting Chk1 may enhance the effects of DNA-damaging agents on cancer progression in such tumors.

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Acknowledgements

We thank I George from the Mount Sinai Flow Cytometry Core Facility for technical support, and Anindita Bhoumik and Ze'ev Ronai for reagents and help with γH2AX staining and Chk2 immunoblots. S Macip is a recipient of a postdoctoral fellowship from the Forchheimer Foundation. A Kosoy is a recipient of a postdoctoral fellowship from the Susan G Komen Breast Cancer Foundation. M O'Connell is a Scholar of the Leukemia and Lymphoma Society. This work was supported by NIH Grants CA80058 and CA85214 (to SAA), CA100076 (to MO) and CA78356 and CA82211 (to SWL).

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Correspondence to S A Aaronson.

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Macip, S., Kosoy, A., Lee, S. et al. Oxidative stress induces a prolonged but reversible arrest in p53-null cancer cells, involving a Chk1-dependent G2 checkpoint. Oncogene 25, 6037–6047 (2006). https://doi.org/10.1038/sj.onc.1209629

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