TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53

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

Supplementary materials

Figure S1 Cell viability (A) and apoptosis (B) in doxorubicin (Dox)-treated non-small cell lung cancer cells before and after p53 knockdown. * represents statistical significance with P<0.05.

Abbreviations: siRNA, small interfering RNA; IC₅₀, 50% inhibitory concentration.

Figure S2 Effect of TopBP1 in non-small cell lung cancer cells.

Abbreviations: TopBP1, topoisomerase IIβ binding protein 1; siRNA, small interfering RNA.

Acknowledgments

This research was supported by the Science Technology Department of Zhejiang Province Welfare projects: role and mechanism of TopBP1 on chemotherapy resistance in non-small cell lung cancer (2013C33100), the National 973 Basic Research Program of China (2013CB911303), Zhejiang Natural Science Foundation: identification and application of new molecular targets phlpp2 of lung cancer (Y15H160213), National Natural Science Foundation of China (81200662), and the Zhejiang Natural Science Foundation (LY14H120004).

Disclosure

The authors report no conflicts of interest in this work.