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CPT1A/2-Mediated FAO Enhancement-A Metabolic Target in Radioresistant Breast Cancer.

  • Author(s): 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
  • et al.
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.

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