TY - JOUR AU - LI Xiao-qin AU - REN Jin AU - CHEN Ping AU - CHEN Yu-jiao AU - WU Min AU - WU Yan AU - CHEN Kang AU - LI Jian PY - 2018 TI - Co-inhibition of Pol η and ATR sensitizes cisplatinresistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair JF - Acta Pharmacologica Sinica; Vol 39, No 8 (August 2018): Acta Pharmacologica Sinica Y2 - 2018 KW - N2 - 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 UR - http://www.chinaphar.com/article/view/9834