title: Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival.
abstract: Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis (TLS) polymerase Q (POLQ) was significantly elevated by exposure of lung cancer cells A549/DR (a cisplatin-resistant A549 cell line) to cisplatin. POLQ expression correlated inversely with homologous recombination (HR) activity. Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin. Thus, co-knockdown of POLQ and HR can efficiently synergize with cisplatin to inhibit A549/DR cell survival by inhibiting DNA DSBs repair. Similar results were observed in A549/DR cells co-depleted of BRCA2 and POLQ following BMN673 (a PARP inhibitor) treatment. Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1. Our results indicate that there is a synthetic lethal relationship between pol θ-mediated DNA repair and HR pathways. Pol θ may be considered as a novel target for lung cancer therapy.
authors.affiliation: Department of Radiation Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Dai
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: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Medical Science, Jiangsu University, Zhenjiang, China.
authors.forename: Tin
authors.initials: T
authors.lastname: Lan
authors.affiliation: Institute of Medical Science, Jiangsu University, Zhenjiang, China.
authors.forename: Yong-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Medical Science, Jiangsu University, Zhenjiang, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Li
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059765:Homologous Recombination / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D000097462:DNA Polymerase theta
chemical_list: D002945:Cisplatin; D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta
keywords: cisplatin-resistance; homologous recombination; lung caner cells; pol θ; translesion synthesis