Inactivation of NADPH Oxidases NOX4 and NOX5 Protects Human Primary Fibroblasts from Ionizing Radiation-Induced DNA Damage

• Type of Material: Article
• Authors: Urbain Weyemi, National Cancer Institute; Christophe E. Redon, National Cancer Institute; Towqir Aziz, National Cancer Institute; Rohini Choudhuri, National Cancer Institute; Daisuke Maeda, National Cancer Institute; Palak R. Parekh, National Cancer Institute; Michael Y. Bonner, Emory University; Jack Arbiser, Emory University; William M. Bonner, National Cancer Institute
• Language: English
• Date: 2015-03-01
• Publisher: Radiation Research Society
• Publication Version: Final Published Version
• Copyright Statement: © 2015 by Radiation Research Society
• Final Published Version (URL): http://dx.doi.org/10.1667/RR13799.1
• Title of Journal or Parent Work: Radiation Research
• Volume: 183
• Issue: 3
• Start Page: 262
• End Page: 270
• Grant/Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health.
• Keywords: INSTABILITY; Biophysics; CELLS; Biology; BLOOD-LYMPHOCYTES; GAMMA-H2AX; Life Sciences & Biomedicine - Other Topics; BONE-MARROW; OXIDATIVE STRESS; INJURY; Science & Technology; Radiology, Nuclear Medicine & Medical Imaging; BIOLOGY; INDUCTION; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Radiology

Abstract

Human exposure to ionizing radiation from medical procedures has increased sharply in the last three decades. Recent epidemiological studies suggest a direct relationship between exposure to ionizing radiation and health problems, including cancer incidence. Therefore, minimizing the impact of radiation exposure in patients has become a priority in the development of future clinical practices. Crucial players in radiation-induced DNA damage include reactive oxygen species (ROS), but the sources of these have remained elusive. To the best of our knowledge, we show here for the first time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are involved in radiation-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in reduced levels of DNA damage as measured by levels of radiation-induced foci, a marker of DNA double-strand breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was substantiated with fulvene-5, a NOXs-specific inhibitor. Moreover, fulvene-5 mitigated radiation-induced DNA damage in human peripheral blood mononuclear cells ex vivo. Our results provide evidence that the inactivation of NOXs protects cells from radiation-induced DNA damage and cell death. These findings suggest that NOXs inhibition may be considered as a future pharmacological target to help minimize the negative effects of radiation exposure for millions of patients each year.