A New Paradigm for Radiation-Induced Persistent Cellular Stress and Genomic Instability in Lung Carcinogenesis
Abstract
Ionizing radiation is an established carcinogen for the lung, which is a sizable organ exposed to the environment, radiosensitive, and a site of frequent secondary neoplasm development in cancer survivors following radiotherapy. Exposure to low doses of radiation is sufficient to damage the DNA and to induce mutations, genome rearrangements and loss, known as genomic instability. In contrast to DNA damage, which is repaired quickly and efficiently in normal cells, genomic instability persists in the progeny of irradiated cells for several generations and for periods that can extend days or weeks, and it has been proposed to be involved in radiation-induced cancer initiation and progression. Genomic instability is also observed in premalignant lung tissue and in the normal tissue surrounding lung tumors, suggesting that this is a common early contributor to lung cancer initiation even when the causal agent is not known. Employing low doses of radiation in a nearly normal lung epithelial cell, which we know reproduces responses observed in the small airways of exposed mice, we have found that in addition to genomic alterations, irradiated cells harbor a persistent stress response driven by p38MAPK that promotes genomic instability and inflammation. Further supporting the relevance of these responses to radiation persisting for a couple of weeks, inhibition of this kinase during the first week following exposure reduces radiation-induced responses and cell transformation. Our proposed research aims to elucidate whether the ubiquitin-dependent modification of proteins that bind to DNA when it is damaged, and define the repair mechanism employed, is a causal mechanism for genomic instability and regulation by p38MAPK. We expect that further studies of the alterations persisting beyond the initial damage caused by radiation and its repair, but before the emergence of late effect, will deliver biomarkers to detect cells with genomic instability and persistent damage as well as novel approaches to target cells with genomic instability to eliminate them or to prevent their emergence. This project is relevant to military Service members, Veterans, and their families as well as the community in general, where the lung is exposed to inhaled or external radiation sources in occupational, accidental or medical settings.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710187
Entities
People
- Paul Doetsch
Organizations
- Emory University
- United States Army