title: Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells.
abstract: It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase ζ, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia-telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear. In this study, we show that REV3 knockdown combined with ATR inhibition further enhance cytotoxicity of cisplatin in NSCLC cells, including cisplatin-sensitive and -resistant cell lines, compared to individual knockdown of REV3 or ATR, which are accompanied by markedly caspase-dependent apoptosis response, pronounced DNA damage accumulation and severe impediment of interstrand crosslink (ICL), and double strand break (DSB) repair. Our results suggest that REV3 knockdown synergize strongly with ATR inhibition to significantly increase sensitivity of cisplatin in NSCLC cells by inhibiting ICL and DSB repair. Thus simultaneously targeting REV3 and ATR may represent one approach to overcome cisplatin resistance and improve chemotherapeutic efficacy in NSCLC treatment.
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: He-Guo
authors.initials: HG
authors.lastname: Jiang
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Su
authors.affiliation: Institute of Medical Science, Jiangsu University, Zhenjiang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Institute of Medical Science, Jiangsu University, Zhenjiang, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.affiliation: Center of Experimental Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; D002945:Cisplatin
keywords: REV3; ataxia telangietasia mutated and Rad-3-related (ATR); cisplatin; non-small cell lung cancer; sensitization