PTBP1 knockdown overcomes the resistance to vincristine and oxaliplatin in drug-resistant colon cancer cells through regulation of glycolysis

Abstract

Drug-resistant cancer cells exhibit increased glycolysis, and targeting glycolysis is considered as a novel strategy to overcome drug resistance. Polypyrimidine tract-binding protein (PTBP1) has been found to be a regulator of glycolysis, however, the role of PTBP1 in drug resistance remains to be elucidated. Herein, we found that PTBP1 was highly expressed in two drug-resistant colon cancer cell lines, vincristine-resistant HCT-8 cell line (HCT-8/V) and oxaliplatin-resistant HCT116 cell line (HCT116/L-OHP). The levels of glucose consumption and lactate production as well as expression of pyruvate kinase M2 isoform (PKM2) and hexokinase II (HK2) were elevated, while PKM1 level was reduced in HCT-8/V and HCT116/L-OHP cells when compared with the HCT-8 and HCT116 cells. PTBP1 knockdown enhanced the sensitivity of HCT-8/V and HCT116/L-OHP cells to vincristine and oxaliplatin, and caused reduction in glucose consumption and lactate production. PKM2 expression, but not HK2, was decreased and PKM1 expression level was increased in cells transfected with si-PTBP1. In addition, PTBP1 overexpression significantly induced glycolysis and reduced drug sensitivity, whereas the effects were attenuated by si-PKM2. Treatment with 2-deoxyglucose (2-DG) also attenuated the effect of PTBP1 overexpression on drug sensitivity. In conclusion, PTBP1 knockdown enhanced the sensitivity of drug-resistant colon cancer cells to vincristine and oxaliplatin through repression of glycolysis. Our study provided a promising therapeutic strategy to overcome drug resistance in colon cancer cells.