Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition

BMC Cancer

Research

Yong Xu¹  Li Yin²  Xia He²  Dan Zong²  Lirong Wu²  Jiajia Gu²  Ning Jiang²  Jiawei Zhou³  Alvan Amos⁴ 

[1] Department of Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, 210009, Nanjing, China;Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, 210009, Nanjing, China;Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 42 Baiziting Road, 210009, Nanjing, China;Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 42 Baiziting Road, 210009, Nanjing, China;Department of Biochemistry, Kaduna State University, PMB 2339, Tafawa Balewa Way, Kaduna, Nigeria;

关键词: Ferroptosis;    Nasopharyngeal carcinoma;    Oxidative stress;    SOD2;    DHODH;   

DOI  :  10.1186/s12885-022-10465-y

 received in 2022-10-29, accepted in 2022-12-20,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundRecurrence due to the development of radioresistance remains a major challenge in the clinical management of nasopharyngeal carcinoma. The objective of this study was to increase the sensitivity of nasopharyngeal carcinoma cells to ionizing radiation by enhancing oxidative stress and ferroptosis caused by disrupting the mitochondrial anti-oxidant enzyme system.MethodsOxidative stress cell model was constructed by SOD2 knockdown using shRNA. The expression and activity of DHODH was suppressed by siRNA and brequinar in SOD2 depleted cells. Protein levels were determined by western blotting and ferroptosis was assessed by C11 BODIPY and malondialdehyde assay. Cell viability was evaluated using CCK-8 assay while radiotoxicity was assessed by colony formation assay. Cellular ATP level was determined by ATP assay kits, ROS was determined by DCFD and DHE, while mitochondrial oxygen consumption was determined by seahorse assay. Data were analyzed by two-tailed independent t-test.ResultsRadiation upregulated SOD2 expression and SOD2 depletion increased cellular O2.−, malondialdehyde, and the fluorescence intensity of oxidized C11 BODIPY. It also resulted in mitochondrial damage. Its depletion decreased colony formation both under ionizing and non-ionizing radiation conditions. The ferroptosis inhibitor, deferoxamine, rescued cell viability and colony formation in SOD2 depleted cells. Cellular level of malondialdehyde, fluorescence intensity of oxidized C11 BODIPY, O2.− level, ATP, and mitochondrial oxygen consumption decreased following DHODH inhibition in SOD2 depleted cells. Cell viability and colony formation was rescued by DHODH inhibition in SOD2 depleted cells.ConclusionInducing oxidative stress by SOD2 inhibition sensitized nasopharyngeal carcinoma cells to ionizing radiation via ferroptosis induction. This was found to be dependent on DHODH activity. This suggests that DHODH inhibitors should be used with caution during radiotherapy in nasopharyngeal carcinoma patients.

【 授权许可】

CC BY   
© The Author(s) 2023

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