Article

Co-inhibition of Pol η and ATR sensitizes cisplatinresistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair

Authors: Xiao-qin LI1, Jin REN1, Ping CHEN2, Yu-jiao CHEN2, Min WU3, Yan WU3, Kang CHEN2, Jian LI1
1 Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
2 Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
3 Institute of Medical Science, Jiangsu University, Zhenjiang 212013, China
Corresponding to: Jian LI: lijian541226@163.com,
DOI: 10.1038/aps.2017.187
Received: 22 October 2017
Accepted: 14 December 2017
Advance online: 31 May 2018

Abstract

For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). However, the capacity to repair DNA interstrand crosslinks (ICLs) and double-strand breaks (DSBs) was significantly enhanced in the A549/DR cell line compared to 3 cisplatin-sensitive cell lines. We found that the protein and mRNA expression levels of Pol η, a Y-family translesion synthesis (TLS) polymerase, were markedly increased upon cisplatin exposure in A549/DR cells compared with A549 cells. Furthermore, intracellular co-localization of Pol η and proliferation cell nuclear antigen (PCNA) induced by cisplatin or cisplatin plus gemcitabine treatment was inhibited by depleting ataxia telangiectasia mutated and Rad-3-related (ATR). Pol η depletion by siRNA sensitized A549/DR cells to cisplatin; co-depletion of Pol η and ATR further increased A549/DR cell death induced by cisplatin or cisplatin plus gemcitabine compared to depletion of Pol η or ATR alone, concomitant with inhibition of DNA ICL and DSB repair and accumulation of DNA damage. No additional sensitization effect of co-depleting Pol η and ATR was observed in A549 cells. These results demonstrate that co-inhibition of Pol η and ATR reverses the drug resistance
Keywords: non-small cell lung cancer; cisplatin; gemcitabine; resistance; polymerase η (Pol η); ATR; DNA damage repair