Nonlinearities in the cellular response to ionizing radiation and the role of p53 therein

Abstract

Many aspects of the cellular response to agents such as ionizing radiation that cause genotoxic and/or oxidative stress exhibit a nonlinear relationship to the applied stress level. These include elements of the antioxidant response and of the damage-signaling pathways that determine cell fate decisions. The wild-type p53 protein, which is mutated in many cancers, coordinates these responses and is a key determinant of this nonlinearity. Indeed, p53 has been referred to as a ‘cellular rheostat’ that favors antioxidant/cytoprotective functions at low stress levels while switching to a pro-oxidant/cytotoxic role under high-stress conditions. For solid tumor-derived cell lines, moderate doses of radiation, typical of those used to generate clonogenic survival curves (i.e. ≤10 Gy), predominantly invoke a dose-dependent cytostatic response. For cancer cell lines with wild-type p53, cytostasis is primarily associated with features of senescence, whereas cancer cells with aberrant p53 primarily undergo endopolyploidization and enlargement. In line with a commentary by Meyn et al. [Int J Radiat Biol. 2009, 85:107–115] concluding that apoptosis is not the primary cause of radiation-induced loss of clonogenicity in solid tumor-derived cell lines, significant levels of apoptosis are typically seen only after higher doses (≥5 Gy) and this is almost all of the delayed (rather than primary) type. Nonlinearity of the oxidative/genotoxic stress response is already apparent in the early antioxidant events activated by transcription factors such as p53 and Nrf2 and the Ref1 transcription coactivator. These cytoprotective pathways serve to minimize damage to important cellular targets caused by reactive oxygen species (ROS) and other electrophiles. After high/supra-lethal levels of stress these inducible antioxidant pathways can be deactivated in a manner that would reinforce the establishment of the pro-oxidant state, resulting in elevated ROS levels and to cytostasis or apoptosis. Understanding the complex regulation of these damage-signaling pathways in relation to the stress levels is important for the optimal utilization of radiation therapy for cancer.

Keywords:

• Ionizing radiation
• DNA damage
• apoptosis
• senescence
• endopolyploidy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the Canadian Breast Cancer Foundation and from the Canadian Institutes of Health Research.

Notes on contributors

David Murray

Dr. David Murray is a Professor of Oncology at the University of Alberta in Edmonton, Canada. He trained in Physical Chemistry before developing an interest in cancer therapeutics while a Research Associate with Dr. Dick Shafer in the Department of Pharmaceutical Chemistry at UCSF. He then spent 13 years at the MD Anderson Cancer Center in Houston, first as a Research Associate in the laboratory of Dr. Ray Meyn then as an independent investigator in the Department of Experimental Radiotherapy. During this period he developed his lasting interest in understanding the cellular responses to anticancer agents such as ionizing radiation and chemotherapy drugs that act primarily through DNA damage. His current interests include investigating how alterations in key components of the DNA damage response pathway, such as the p53 protein which is mutated/altered in many human cancers, might be exploited to make these therapies more specific for cancer versus normal cells.

Razmik Mirzayans

Dr. Razmik Mirzayans is a Clinical Professor in the Department of Oncology/Division of Experimental Oncology, Faculty of Medicine & Dentistry, University of Alberta. His research since the early 1980s has contributed to our understanding of the mechanisms that control the responses of human normal and solid tumor-derived cell lines to genotoxic agents. Specifically, he has focused on studying the role of the ATM-p53-p21(WAF1) signaling pathway in activating ‘early’ responses (e.g. DNA repair, cell cycle checkpoints) and ‘late’ responses (e.g. dormancy through premature senescence) following exposure to ionizing radiation and chemotherapeutic agents, in an attempt to explore the basis for the radio/chemo-resistant phenotype displayed by some cancer cell lines.