Drug Design, Development and Therapy (Sep 2016)
TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53
Abstract
Yinxiang Lv,1,* Yanan Huo,2,* Xican Yu,1 Rongrong Liu,3 Shufen Zhang,3 Xiaoxiao Zheng,3 Xianning Zhang 3 1Department of Oncology, Xinchang People’s Hospital, Shaoxing, 2Eye Centre, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 3Department of Cell Biology and Medical Genetics, Research Center of Molecular Medicine, National Education Base for Basic Medical Sciences, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Resistance to chemotherapeutic drugs is a major obstacle in non-small cell lung cancer (NSCLC) therapy. The molecular determinants of NSCLC resistance to doxorubicin are unknown. In the present study, we investigated whether topoisomerase IIβ binding protein 1 (TopBP1) was involved in the chemoresistance to doxorubicin in NSCLC cancer. We found that p53-deficient lung cancer cells (NCI-H1299) displayed the greatest resistance to doxorubicin compared with NCI-H358, A549, and HCC827 cells with p53 expression. The expression of TopBP1 was significantly higher in NCI-H1299 cells than the other three tumor cell lines. In addition, TopBP1 knockdown with specific small interfering RNA in NCI-H1299 cells enhanced the doxorubicin chemosensitivity and decreased the expression of p53 in the presence of doxorubicin. After doxorubicin administration, co-immunoprecipitation assay showed that TopBP1 promoted the expression of p53 in NCI-H1299 cells. These results for the first time demonstrated that TopBP1 plays an important role in NSCLC chemoresistance via upregulation of p53. Therefore, inhibition of TopBP1, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant NSCLC. Keywords: non-small cell lung cancer, drug resistance, TopBP1, p53
