Dataset Information

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

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.

SUBMITTER: Han S

PROVIDER: S-EPMC6873486 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Han Shujun S Wei Ryan R Zhang Xiaodi X Jiang Nian N Fan Ming M Huang Jie Hunter JH Xie Bowen B Zhang Lu L Miao Weili W Butler Ashley Chen-Ping AC Coleman Matthew A MA Vaughan Andrew T AT Wang Yinsheng Y Chen Hong-Wu HW Liu Jiankang J Li Jian Jian JJ

Frontiers in oncology 20191115

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 a ...[more]

PMID: 31803610

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Project description:BackgroundCancer-associated fibroblasts (CAFs) are the predominant residents in the breast tumor microenvironment. In our work, we found activation of DNA damage-independent ATM (oxidized ATM), enhanced glycolysis and aberrant metabolism-associated gene expressions in breast CAFs. Nevertheless, whether and how oxidized ATM regulates the glycolytic activity of CAFs keep in unveil. Recently, a reverse Warburg effect was observed in tumor tissues, in which host cells (such as CAFs, PSCs) in the tumor microenvironment have been found to "fuel" the cancer cells via metabolites transfer. However, the molecular mechanisms of the metabolites from stromal cells playing a role to the progression of cancer cells remain to be determined.MethodsOxidized ATM activation in stromal CAFs was assessed by western blotting and immunofluorescence. The increased glycolytic ability of CAFs was validated by measurements of OCR and ECAR and detections of glucose consumption and lactate production. Kinase assay and western blotting were performed to confirm the phosphorylation of GLUT1. The membrane location of phosphorylated GLUT1 was determined by biotin pull-down assay and immunofluorescence staining. The regulation of PKM2 through oxidized ATM was evaluated by western blots. In addition, the impact of lactate derived from hypoxic CAFs on cancer cell invasion was investigated both in vitro (transwell assays, western blots) and in vivo (orthotopic xenografts).FindingsHypoxia-induced oxidized ATM promotes glycolytic activity of CAFs by phosphorylating GLUT1 at S490 and increasing PKM2 expression. Moreover, lactate derived from hypoxic CAFs, acting as a metabolic coupling between CAFs and breast cancer cells, promotes breast cancer cell invasion by activating the TGFβ1/p38 MAPK/MMP2/9 signaling axis and fueling the mitochondrial activity in cancer cells.InterpretationOur work shows that oxidized ATM-mediated glycolysis enhancement in hypoxic stromal fibroblasts plays an essential role in cancer cell invasion and metastasis and may implicate oxidized ATM as a target for breast tumor treatment. FUND: This research was supported by National Natural Science Foundation of China.

Project description:BackgroundRadiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance.MethodsRadioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses.ResultsProliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity.ConclusionsThis is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.

Dataset Information

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

Publications

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

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