title: FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: He
authors.affiliation: Changzhou No. 7 People's Hospital, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Luo
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Yilan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Kathera
authors.affiliation: Southern University of Science and Technology of China, Shenzhen, China.
authors.forename: Lingjie
authors.initials: L
authors.lastname: Liu
authors.affiliation: Changzhou No. 7 People's Hospital, China.|School of Pharmaceutical Engineering and Life Sciences, Changzhou University, China.
authors.forename: Ziheng
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, China.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D002945:Cisplatin
keywords: cisplatin resistance; flap endonuclease 1; lung cancer; targeted therapy