Ionizing Radiation induction of cholesterol biosynthesis in Lung tissue

• Type of Material: Article
• Authors: Erica Werner, Emory University; Andrew Alter, Emory University; Qiudong Deng, Emory University; Eric Dammer, Emory University; Ya Wang, Emory University; David Yu, Emory University; Duc M. Duong, Emory University; Nicholas Seyfried, Emory University; Paul Doetsch, Emory University
• Language: English
• Date: 2019-08-29
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-48972-x
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 12546
• End Page: 12546
• Grant/Funding Information: This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute comprehensive cancer center grant, P30CA138292, the Emory Integrated Proteomics Core and the Winship Research Pathology Core.; This work was funded by NASA-NSCOR grant NNX11AC3OG (Y.W.), DoD grant W81XWH-17-1-0187 to P.D./E.W.; This work was also supported by the US National Institute of Health Intramural Research Program Projects Z1AES103328 to (P.D.).
• Keywords: EXPOSURE; DAMAGE; Multidisciplinary Sciences; DISEASE; CELLS; Science & Technology - Other Topics; Science & Technology; CANCER; METABOLISM
• Research Categories: Health Sciences, Oncology; Chemistry, Radiation

Abstract

While evidence supporting the notion that exposures to heavy ion radiation increase the risk for cancer and other disease development is accumulating, the underlying biological mechanisms remain poorly understood. To identify novel phenotypes that persist over time that may be related to increased disease development risk, we performed a quantitative global proteome analysis of immortalized human bronchial epithelial cells (HBEC3-KT) at day 7 post exposure to 0.5 Gy Fe ion (600 MeV/nucleon, Linear Energy Transfer (LET) = 175 keV/μm). The analysis revealed a significant increase in the expression of 4 enzymes of the cholesterol biosynthesis pathway. Elevated expression of enzymes of the cholesterol pathway was associated with increased cholesterol levels in irradiated cells and in lung tissue measured by a biochemical method and by filipin staining of cell-bound cholesterol. While a 1 Gy dose of Fe ion was sufficient to induce a robust response, a dose of 5 Gy X-rays was necessary to induce a similar cholesterol accumulation in HBEC3-KT cells. Radiation-increased cholesterol levels were reduced by treatment with inhibitors affecting the activity of enzymes in the biosynthesis pathway. To examine the implications of this finding for radiotherapy exposures, we screened a panel of lung cancer cell lines for cholesterol levels following exposure to X-rays. We identified a subset of cell lines that increased cholesterol levels in response to 5 Gy X-rays. Survival studies revealed that statin treatment is radioprotective, suggesting that cholesterol increases are associated with cytotoxicity. In summary, our findings uncovered a novel radiation-induced response, which may modify radiation treatment outcomes and contribute to risk for radiation–induced cardiovascular disease and carcinogenesis.