Corosolic acid reduces 5‑FU chemoresistance in human gastric cancer cells by activating AMPK.

Abstract

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents for gastric cancer. Resistance to 5-FU-based chemotherapy remains the major obstacle in the treatment of gastric cancer. A growing body of evidence has suggested that adenosine monophosphate-activated protein kinase (AMPK) is pivotal for chemoresistance. However, the mechanism by which AMPK regulates the chemosensitivity of gastric cancer remains unclear. In the present study, how corosolic acid enhanced the chemosensitivity of gastric cancer cells to 5-FU via AMPK activation was investigated. A 5-FU-resistant gastric cancer cell line (SNU-620/5-FUR) was established, which had a marked increase in thymidine synthase (TS) expression but reduced AMPK phosphorylation when compared with the parental cell line, SNU-620. AMPK regulation by 5-aminoimidazole-4-carboxamide ribonucleotide or compound c was revealed to be markedly associated with TS expression and 5-FU-resistant cell viability. In addition, corosolic acid activated AMPK, and decreased TS expression and the phosphorylation of mammalian target of rapamycin/4E-binding protein 1 in a dose-dependent manner. Corosolic acid treatment significantly reduced cell viability while compound c reversed corosolic acid-induced cell growth inhibition. The 5-FU-resistance sensitization effect of corosolic acid was determined by the synergistic reduction of TS expression and inhibition of cell viability in the presence of 5-FU. The corosolic acid-induced AMPK activation was markedly increased by additional 5-FU treatment, while compound c reversed AMPK phosphorylation. In addition, compound c treatment reversed corosolic acid-induced apoptotic markers such as capase-3 and PARP cleavage, and cytochrome c translocation to cytosol, in the presence of 5-FU. Corosolic acid treatment in the presence of 5-FU induced an increase in the apoptotic cell population based on flow cytometry analysis. This increase was abolished by compound c. In conclusion, these results implied that corosolic acid may have therapeutic potential to sensitize the resistance of gastric cancer to 5-FU by activating AMPK.