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

• Published in: Cancer letters 2022-01, Vol.524, p.268-283
• Main Authors: Zhang, Jingjing, Wu, Qiong, Zhu, Lucheng, Xie, Shujun, Tu, Linglan, Yang, Yuhong, Wu, Kan, Zhao, Yanyan, Wang, Yuqing, Xu, Yasi, Chen, Xueqin, Ma, Shenglin, Zhang, Shirong
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Antibodies; Apoptosis; Ataxia Telangiectasia Mutated Proteins - genetics; ATM; Cell culture; Cell cycle; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - genetics; Cell Survival - drug effects; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA Damage - radiation effects; DNA damage response; DNA repair; DNA Repair - genetics; DNA Repair - radiation effects; Homologous recombination; Homologous recombination repair; Humans; Ionizing radiation; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; MRE11 Homologue Protein - genetics; MRE11 protein; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Non-small cell lung carcinoma; Phenotypes; Phosphorylation; Phosphorylation - radiation effects; Plasmids; Proteins; Rad51 Recombinase - genetics; Radiation therapy; Radiation Tolerance - genetics; Radiation, Ionizing; Radioresistance; Radiosensitivity; Serine proteinase; Serine proteinase inhibitors; Serpin E2 - genetics; SERPINE2; Small cell lung carcinoma; Tumors; Viral infections
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2021.10.001

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. •SERPINE2 knockdown inhibits radioresistance and DNA damage repair by mediating RAD51 in lung cancer.•SERPINE2 promotes ATM phosphorylation by directly interacting with ATM in HR-mediated DNA repair.•SERPINE2 shRNA reduces IR-induced G2/M arrest, and inhibits migration and invasion in vitro.•High SERPINE2 expression is correlated with a poor prognosis in lung adenocarcinomas.