Poly(C)-binding protein 1 mediates drug resistance in colorectal cancer

Abstract

Oxaliplatin (L-OHP) is standard treatment for colorectal cancer. However, resistance to L-OHP often leads to treatment failure or cancer relapse. Understanding of the mechanism underlying L-OHP resistance is important to overcome the resistance and improve colorectal cancer treatment. This study aimed to identify new proteins that mediates L-OHP resistance in colorectal cancer and elucidate their mode of function. HT-29 cells were exposed to gradually increased concentration of L-OHP to select L-OHP resistant HT-29/L-OHP cell line. Proteomic analysis of HT-29 and HT-29/L-OHP cells were performed to identify differentially expressed proteins, including Poly(C)-binding protein 1 (PCBP1). PCBP1 expression level in 20 cases of L-OHP sensitive patients and 20 cases of L-OHP refractory patients was analyzed by immunohistochemistry. Chemoresistance and Akt activation in HT-29 and HT-29/L-OHP cells were analyzed by MTT assay and Western blot analysis. We identified 37 proteins showing differential expression in HT-29/L-OHP and HT-29 cells. In particular, PCBP1 protein level increased 15.6 fold in HT-29/L-OHP cells compared to HT-29 cells. Knockdown of PCBP1 sensitized HT-29/L-OHP and HT-29 cells to L-OHP, while overexpression of PCBP1 increased L-OHP resistance in HT-29 cells. In addition, PCBP1 expression was significantly higher in tumor samples from L-OHP refractory patients than in those from L-OHP responsive patients. Furthermore, we found that knockdown of PCBP1 inhibited the activation of Akt in HT-29/L-OHP and HT-29 cells. In conclusion, our findings suggest that PCBP1 is a molecular marker of L-OHP resistance in colorectal cancer and a promising target for colorectal cancer therapy.