AUTHOR=Han Shujun , Wei Ryan , Zhang Xiaodi , Jiang Nian , Fan Ming , Huang Jie Hunter , Xie Bowen , Zhang Lu , Miao Weili , Butler Ashley Chen-Ping , Coleman Matthew A. , Vaughan Andrew T. , Wang Yinsheng , Chen Hong-Wu , Liu Jiankang , Li Jian Jian TITLE=CPT1A/2-Mediated FAO Enhancement—A Metabolic Target in Radioresistant Breast Cancer JOURNAL=Frontiers in Oncology VOLUME=9 YEAR=2019 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01201 DOI=10.3389/fonc.2019.01201 ISSN=2234-943X ABSTRACT=

Tumor cells, including cancer stem cells (CSCs) resistant to radio- and chemotherapy, must enhance metabolism to meet the extra energy demands to repair and survive such genotoxic conditions. However, such stress-induced adaptive metabolic alterations, especially in cancer cells that survive radiotherapy, remain unresolved. In this study, we found that CPT1 (Carnitine palmitoyl transferase I) and CPT2 (Carnitine palmitoyl transferase II), a pair of rate-limiting enzymes for mitochondrial fatty acid transportation, play a critical role in increasing fatty acid oxidation (FAO) required for the cellular fuel demands in radioresistant breast cancer cells (RBCs) and radiation-derived breast cancer stem cells (RD-BCSCs). Enhanced CPT1A/CPT2 expression was detected in the recurrent human breast cancers and associated with a worse prognosis in breast cancer patients. Blocking FAO via a FAO inhibitor or by CRISPR-mediated CPT1A/CPT2 gene deficiency inhibited radiation-induced ERK activation and aggressive growth and radioresistance of RBCs and RD-BCSCs. These results revealed that switching to FAO contributes to radiation-induced mitochondrial energy metabolism, and CPT1A/CPT2 is a potential metabolic target in cancer radiotherapy.