He Lingfeng, Luo Libo, Zhu Hong, Yang Huan, Zhang Yilan, Wu Huan, Sun Hongfang, Jiang Feng, Kathera Chandra S, Liu Lingjie, Zhuang Ziheng, Chen Haoyan, Pan Feiyan, Hu Zhigang, Zhang Jing, Guo Zhigang
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
Changzhou No. 7 People's Hospital, China.
Mol Oncol. 2017 Jun;11(6):640-654. doi: 10.1002/1878-0261.12058. Epub 2017 May 12.
Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells. Suppression of FEN1 resulted in decreased DNA replication and accumulation of DNA damage, which subsequently induced apoptosis. Manipulating the amount of FEN1 altered the response of lung cancer cells to chemotherapeutic drugs. A small-molecule inhibitor (C20) was used to target FEN1 and this enhanced the therapeutic effect of cisplatin. The FEN1 inhibitor significantly suppressed cell proliferation and induced DNA damage in lung cancer cells. In mouse models, the FEN1 inhibitor sensitized lung cancer cells to a DNA damage-inducing agent and efficiently suppressed cancer progression in combination with cisplatin treatment. Our study suggests that targeting FEN1 may be a novel and efficient strategy for a tumor-targeting therapy for lung cancer.
肺癌是全球癌症死亡的主要原因之一。由于癌细胞的耐药性，化疗的治疗效果有限，这仍然是癌症治疗中的一个挑战。在这项研究中，我们发现瓣状核酸内切酶1（FEN1）在肺癌细胞中过表达。FEN1是DNA修复系统碱基切除修复途径的主要组成部分，在通过DNA复制和修复维持基因组稳定性方面发挥重要作用。我们表明FEN1对肺癌细胞的快速增殖至关重要。抑制FEN1导致DNA复制减少和DNA损伤积累，随后诱导细胞凋亡。操纵FEN1的量改变了肺癌细胞对化疗药物的反应。一种小分子抑制剂（C20）被用于靶向FEN1，这增强了顺铂的治疗效果。FEN1抑制剂显著抑制肺癌细胞的增殖并诱导DNA损伤。在小鼠模型中，FEN1抑制剂使肺癌细胞对DNA损伤诱导剂敏感，并与顺铂治疗联合有效地抑制癌症进展。我们的研究表明，靶向FEN1可能是一种针对肺癌的新型高效肿瘤靶向治疗策略。
