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

• 来源期刊: 中国药理学报（英文版）
• 关键词: non-small cell lung cancer cisplatin gemcitabine resistance polymerase η (Pol η) ATR DNA damage repair
• 年，卷（期）: 2018,（8）
• 页码范围: 1359-1372
• 页数: 14页
• 语种: 英文
• DOI: 10.1038/aps.2017.187

摘要

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 rl 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 rη and ATR was observed in A549 cells.These results demonstrate that co-inhibition of Pol η and ATR reverses the drug resistance of cisplatin-resistant NSCLC cells by blocking the repair of DNA ICLs and DSBs induced by cisplatin or cisplatin plus gemcitabine.