Sirt3 Regulates Radioresistance of Non-small Cell Lung Cancer through ATM-Chk2 Pathway

Abstract With high incidence and mortality, non-small cell lung cancer (NSCLC) represent 85-90% in all lung cancer patients. In addition to surgery and chemotherapy, radiotherapy is an indispensable approach for cancer treatment. 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. Briefly, survival as well as apoptosis assay were used to determine the cellular radiosensitivity, and an in situ lung cancer model to test the radiosensitivity in vivo. Firstly, our data show that Sirt3 is upregulated in NSCLC cell lines, as well as tissues compared with normal tissues. Then we generated Sirt3 knockdown cells and overexpression cells and found that Sirt3 knockdown increased radiosensitivity, while Sirt3 overexpression caused resistance. 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. In conclusion, our findings identified a significant role of Sirt3 in radioresistanct of NSCLC, which provides novel mechanism as well as target for radiotherapy.