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

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.

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

“…It is well-established that tumor radiation sensitivity greatly varies among individuals. As a result, some drugs have been reported to target multiple sensitivity or resistance factors (18,(22)(23)(24). Tumor radiosensitivity is mainly related to the intrinsic sensitivity of tumor cells and the cancer microenvironment (25).…”

PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair

“…With the continuous development of biotechnology, complex models including carcinogenic induction model, genetically engineered mouse model and PDX model have emerged, which can make up for the above de ciencies. (39)(40)(41) In this study, we rstly used CDX model, and found that tumors derived from PRDM15-KD cells are more sensitive to radiotherapy than tumor derived from PRDM15-NC cells. However, neither the subcutaneous model nor in situ rectal cancer model can re ect the real environment.…”

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

“…In another study, upregulation of serine proteinase inhibitor clade E member 2 (SERPINE2) and Sirtuin 3 acts as a regulator of radiosensitivity in lung cancer and is directly involved in the DNA repair mechanism by facilitating the phosphorylation of HR-mediated DSBs’ repair. Knocking down SERPINE2 in radioresistant cells made them more radiosensitive [ 157 , 158 ]. Moreover, knocking down Sirt3 can arrest the cell cycle and activate the ATM-Chk2 pathway over irradiation [ 158 ].…”

“…Knocking down SERPINE2 in radioresistant cells made them more radiosensitive [ 157 , 158 ]. Moreover, knocking down Sirt3 can arrest the cell cycle and activate the ATM-Chk2 pathway over irradiation [ 158 ]. Transfecting an integrin beta-1 (ITGB1) short hairpin RNA (shRNA) increased radiation-induced DNA damage and arresting of the G2/M phase.…”