SERPINE2/PN-1 regulates the DNA damage response and radioresistance by activating ATM in lung cancer.

Abstract

Although the DNA damage response (DDR) is associated with the radioresistance characteristics of lung cancer cells, the specific regulators and underlying mechanisms of the DDR are unclear. Here, we identified the serine proteinase inhibitor clade E member 2 (SERPINE2) as a modulator of radiosensitivity and the DDR in lung cancer. Cells exhibiting radioresistance after ionizing radiation show upregulation of SERPINE2, and SERPINE2 knockdown improves tumor radiosensitivity in vitro and in vivo. Functionally, SERPINE2 deficiency causes a reduction in homologous recombination repair, rapid recovery of cell cycle checkpoints, and suppression of migration and invasion. Mechanistically, SERPINE2 knockdown inhibits the accumulation of p-ATM and the downstream repair protein RAD51 during DNA repair, and RAD51 can restore DNA damage and radioresistance phenotypes in lung cancer cells. Furthermore, SERPINE2 can directly interact with MRE11 and ATM to facilitate its phosphorylation in HR-mediated DSB repair. In addition, high SERPINE2 expression correlates with dismal prognosis in lung adenocarcinoma patients, and a high serum SERPINE2 concentration predicts a poor response to radiotherapy in non-small cell lung cancer patients. In summary, these findings indicate a novel regulatory mechanism by which SERPINE2 modulates the DDR and radioresistance in lung cancer.

• Authors: Jingjing Zhang, Qiong Wu, Lucheng Zhu, Shujun Xie, Linglan Tu, Yuhong Yang, Kan Wu, Yanyan Zhao, Yuqing Wang, Yasi Xu, Xueqin Chen, Shenglin Ma, Shirong Zhang
• Journal: Cancer letters (Cancer Lett) Vol. 524 Pg. 268-283 (01 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34648881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• MRE11 protein, human
• SERPINE2 protein, human
• Serpin E2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Rad51 Recombinase
• MRE11 Homologue Protein

Topics

• Ataxia Telangiectasia Mutated Proteins (genetics)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (genetics)
• Cell Survival (drug effects)
• DNA Damage (drug effects, radiation effects)
• DNA Repair (genetics, radiation effects)
• Humans
• Lung Neoplasms (genetics, pathology, radiotherapy)
• MRE11 Homologue Protein (genetics)
• Neoplasm Invasiveness (genetics, pathology)
• Phosphorylation (radiation effects)
• Rad51 Recombinase (genetics)
• Radiation Tolerance (genetics)
• Radiation, Ionizing
• Serpin E2 (genetics)