TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2.

Abstract

Cisplatin is commonly used for lung cancer treatment. However, acquire resistance to cisplatin results in reduced therapy efficacy. Tripartite motif-containing 59 (TRIM59), acting as an oncogene in non-small cell lung cancer (NSCLC), induces chemoresistance in breast cancer cells. Here, the mechanism by which TRIM59 mediates cisplatin resistance was determined. We demonstrated that cisplatin-resistant NSCLC cell line (A549/DDP) had higher expression of TRIM59 than its parental cell line (A549). As indicated by cell apoptosis assay, TRIM59 overexpression in A549 cells resulted in an increased cisplatin resistance, while TRIM59 downregulation in A549/DDP cells led to an decreased cisplatin resistence. A549/DDP cells with TIMR59 knockdown was more sensitive to cisplatin treatment in a xenograft model. Moreover, A549/DDP cells exhibited increased glucose uptake, lactate production, and hexokinase 2 (HK2, an important glycolytic pathway enzyme) expression than A549 cells. The glycolysis was increased by TRIM59 overexpression in A549 cell, and decreased by TRIM59 knockdown in A549/DDP cells. 3-Bromopyruvate Acid (3-BrPA), an inhibitor of HK2, significantly enhanced cisplatin-sensitivity in A549 cells overexpressing TRIM59. Furthermore, both TRIM59 and HK2 expression was higher in cisplatin-resistant NSCLC tissues than in non-resistant ones, and mRNA expression of these two molecules was positively correlated in NSCLC tissues. The changes of PTEN and phosphorylation of AKT (p-AKT), a critical upstream regulator of HK2, were also consistent with HK2 expression. Immunoprecipiation experiments showed the interaction between TRIM59 and PTEN in A549/DDP cells, and that TRIM59 knockdown suppressed the ubiquitination of PTEN. Collectively, the present study indicates that TRIM59 knockdown reverses high glycolysis rate and cisplatin resistance in A549/DDP cells through the regulation of PTEN/AKT/HK2 and may provide insights into overcoming cancer resistance to cisplatin treatment.