Abstract 6180: The role of radiation dose-dependent enhancement of fatty acid oxidation on radiation surviving/resistant lung cancer cells

Abstract

Abstract Objective: Radiotherapy plays a critical role in the integrated management of lung cancer. However, radioresistance limits the long-term control. Exploring the dynamic changes of metabolic reprogramming in radiation surviving/resistance lung cancer cells is helpful to clarify the metabolic mechanism of radiation resistance and to develop new targets for intervention and early detection. Methods: Multiple lung cancer cell lines were irradiated with different doses (2Gy × 20F, 2Gy × 30F, 2Gy × 40F) in conventional dose fractionation. The cellular radiosensitivity was verified by colony formation assay and neutral comet assay. Cell proliferation ability was determined by EdU assay. Metabonomic analysis was used to identify the differentially expressed metabolites between high-dose radiation-resistant cells and their parent cells. Lipid droplet content was detected by Oil Red O staining. Cell oxygen consumption rate (OCR) was measured by Seahorse XF24e analyzer. Western blot was used to detect the expression of metabolic enzymes. The growth of xenograft tumors from these cell lines in BALB/c nude mice were measured after the treatment of radiation (2Gy × 5F), Etomoxir, or radiation combined with Etomoxir. Results: Compared with parent cells, the radioresitance of surviving/resistant lung cancer cells after different doses of radiation was significantly increased with the increase of radiation exposure. Oil Red O staining showed that fatty deposition of radiation surviving/resistant cells was obviously higher than their parent cells, and more fatty deposition in cells received higher dose of radiation. The ketone body metabolism-related substances, including acetoacetic acid, a metabolite of FAO, were significantly enriched in high-dose radiation-resistant lung cancer cells. The expression of carnitine palmitoyltransferase1 (CPT1) and the OCR in radiation surviving/resistant lung cancer cells were also radiation-dose dependently increased. Etomoxir, an inhibitor of fatty acid oxidation, significantly enhanced the radiosensitivity and decreased the OCR and DNA repair ability of various surviving/resistant lung cancer cells exposed to radiation. We further confirmed that Etomoxir could significantly inhibit proliferation of radiation surviving/resistant cells in vivo, which also presented with radiation-dose dependent model. Conclusions: The establishment of equidifferent dose radiation surviving/resistance lung cancer cell lines in this study provides a preclinical research model for exploring the mechanism of dose-dependent radiation resistance. The enhancement of radiation dose-dependent FAO promotes radiation surviving/resistance of lung cancer cells. CPT1A, a key metabolic enzyme mediating FAO, may be a potential target for treatment of radiation resistant lung cancer. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033. Citation Format: Xiaoxia Zhu, Shangbiao Li, Lijuan Wang, Zhihao Zheng. The role of radiation dose-dependent enhancement of fatty acid oxidation on radiation surviving/resistant lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6180.