J Cancer 2021; 12(18):5464-5472. doi:10.7150/jca.53173 This issue

Research Paper

Sirt3 Promoted DNA Damage Repair and Radioresistance Through ATM-Chk2 in Non-small Cell Lung Cancer Cells

Kun Cao#1, Yuanyuan Chen#1, Songyun Zhao#2, Yijuan Huang1,4, Tingting Liu1, Hu Liu1, Bailong Li1, Jianguo Cui1, Jianming Cai1,3, Chong Bai2✉, Yanyong Yang1✉, Fu Gao1✉

1. Department of Radiation Medicine, Faculty of Naval Medicine, Navy Military Medical University; Shanghai, China.
2. Department of Respiratory and Critical Care Medicine, Changhai Hospital, Navy Military Medical University; Shanghai, China.
3. School of Public Health & Management Wenzhou Medical University, P.R China.
4. The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University
#These authors contributed equally to this work.

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Citation:
Cao K, Chen Y, Zhao S, Huang Y, Liu T, Liu H, Li B, Cui J, Cai J, Bai C, Yang Y, Gao F. Sirt3 Promoted DNA Damage Repair and Radioresistance Through ATM-Chk2 in Non-small Cell Lung Cancer Cells. J Cancer 2021; 12(18):5464-5472. doi:10.7150/jca.53173. Available from https://www.jcancer.org/v12p5464.htm

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Abstract

Graphic abstract

Objective: Radiotherapy is an indispensable approach for lung cancer, especially for non-small cell lung cancer (NSCLC) with high incidence and mortality. However, cellular resistance to ionizing radiation often results in failure in treatment. In this study, we aimed to investigate the role of Sirt3 in radiotherapy on NSCLC.

Materials and Methods: Resected samples from 80 pairs of lung cancer was used to prepare tissue array and Sirt3 was stained with immunochemical method. Cell survival as well as apoptosis assay were used to determine the cellular radiosensitivity. Moreover, DNA damage was evaluated by using γ-H2AX foci. Finally, an in situ lung cancer model to test the radiosensitivity in vivo.

Results: Sirtuin 3 (Sirt3) was found upregulated in NSCLC cell lines, as well as lung cancer tissues compared with normal tissues. Knockdown of Sirt3 significantly increased radiation-induced cell apoptosis, and increased cell survival efficacy. In contrast, Sirt3 overexpression promoted radioresistance in lung cancer cells. Sirt3 knockdown also aggravated the G2/M cell cycle arrest caused by irradiation. Furthermore, Sirt3 was found to be critical for the activation of ATM-Chk2 pathway upon irradiation. Finally, our in vivo model showed that targeting Sirt3 significantly sensitized lung cancer to radiotherapy.

Conclusion: In conclusion, our findings identified a significant role of Sirt3 in radioresistanct of NSCLC, which provides novel mechanism as well as target for radiotherapy.

Keywords: Sirt3, DNA damage repair, radiosensitivity, lung cancer