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.
Highlights
Radiation therapy (RT) is the major modality in treatment of solid cancer, including breast cancer (BC), with reported clinical benefits [1, 2]
Enhanced lipid turnover rate was detected in MCF7/C6 cells loaded with free fatty acid (FFA), which was contrasted with the markedly accumulation of FFA in the wild type MCF7 cells (Figure 1C), indicating enhanced fatty acid oxidation (FAO) metabolism in resistant breast cancer cells (RBCs) cells
These results indicate that reprograming mitochondrial FAO contributes to BC radioresistance and worse prognosis
Summary
Radiation therapy (RT) is the major modality in treatment of solid cancer, including breast cancer (BC), with reported clinical benefits [1, 2]. We have reported that mitochondrial MnSOD activity is required for radioresistance in BC cells [14, 15] and radiation can enhance mitochondrial OXPHOS in tumor cells [16]. Mitochondrial energy output is required for nuclear DNA repair after IR [24], and mitochondrial FAO is linked with BC metastasis [25, 26]. With such a flexible adaptive energy metabolism detected in the malignant cells [13, 27], it is reasonable to look into the deep mechanistic insights of reprogramming mitochondrial bioenergetics in aggressive tumors, especially the RBCs
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