2. Academic Validation
  3. Acetyl-CoA Acetyltransferase 2 Confers Radioresistance by Inhibiting Ferroptosis in Esophageal Squamous Cell Carcinoma

Acetyl-CoA Acetyltransferase 2 Confers Radioresistance by Inhibiting Ferroptosis in Esophageal Squamous Cell Carcinoma

  • Int J Radiat Oncol Biol Phys. 2023 May 25;S0360-3016(23)00519-9. doi: 10.1016/j.ijrobp.2023.05.031.
Jinghua Heng 1,  Zhimao Li 2,  Luxin Liu 3,  Zhenyuan Zheng 4,  Yaqi Zheng 2,  Xiue Xu 2,  Liandi Liao 2,  Hongyao Xu 5,  Hecheng Huang 5,  Enmin Li 6,  Liyan Xu 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: 19jhheng@stu.edu.cn.
  • 2 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 3 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 4 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China; The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China.
  • 5 Department of Radiation Oncology, Shantou Central Hospital, Shantou, 515041, China.
  • 6 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: nmli@stu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: lyxu@stu.edu.cn.
PMID: 37244629 DOI: 10.1016/j.ijrobp.2023.05.031
Abstract

Purpose: The overall survival of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiotherapy (CCRT) resistance. The aim of this study is to use proteomics to identify a protein related to radiotherapy resistance and explore its molecular mechanisms.

Methods and materials: Proteomic data of pretreatment biopsy tissues from 18 ESCC patients, who underwent CCRT (complete response (CR) group, n = 8; incomplete response (<CR) group, n = 10), was collected and combined with ESCC proteomic data from iProx (n = 124) to identify candidate proteins that confer resistance to CCRT. Subsequently, 125 paraffin-embedded biopsies were used for immunohistochemical validation. Colony formation assays, following ionizing radiation (IR), of acetyl-CoA acetyltransferase 2 (ACAT2)-overexpressing, -knockdown or -knockout ESCC cells were used to determine the effects of ACAT2 on radioresistance. ROS, C11-BODIPY and western blotting were employed to reveal the potential mechanism of ACAT2-mediated radioresistance after IR.

Results: Enrichment analysis of differentially-expressed proteins (<CR vs. CR) showed that the pathways of molecules conferring CCRT resistance in ESCC were related to lipid metabolism, whereas molecules conferring CCRT sensitivity were mainly related to immunity pathways. ACAT2 was selected from proteomics and validated by immunohistochemistry as a risk factor for reduced overall survival and CCRT or radiotherapy resistance among ESCC patients. ACAT2 overexpression conferred resistance to IR treatment, whereas ACAT2 knockdown or knockout conferred IR sensitivity. ACAT2 knockout cells were prone to having elevated ROS production, enhanced lipid peroxidation, and reduced levels of Glutathione Peroxidase 4 (GPX4) after IR compared with irradiated wildtype cells. ACAT2 knockout cells could be rescued from IR-mediated toxicity by ferrostatin-1 and liproxstatin.

Conclusion: ACAT2 overexpression confers radioresistance by inhibiting Ferroptosis in ESCC, suggesting ACAT2 could be a potential biomarker of poor radiotherapeutic response and a therapeutic target for enhancing radiosensitivity of ESCC.

Keywords

ACAT2; CCRT; esophageal squamous cell carcinoma; ferroptosis; proteomics; radioresistance.

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