Salinomycin reduces epithelial-mesenchymal transition-mediated multidrug resistance by modifying long noncoding RNA HOTTIP expression in gastric cancer cells.

Abstract

Chemotherapy is the main treatment for advanced gastric cancer. However, the emergence of multidrug resistance (MDR) has become a major obstacle in chemotherapy in many tumors, including gastric cancer. Epithelial-mesenchymal transition (EMT), which is considered an important process in cancer development, also contributes toward tumor MDR. Salinomycin, an EMT blocker, shows broad-spectrum antitumor and chemosensitization properties. Here, we hypothesized that salinomycin could reverse the MDR of SGC7901/cisplatin (CDDP) gastric cancer cell by inhibiting EMT and further explored its possible underlying mechanisms. Our results indicated higher 50% inhibiting concentration (IC50) and stronger migration capacity in SGC7901/CDDP than in SGC7901 cells, whereas salinomycin could reduce the IC50 (50% inhibition of the concentration of chemodrugs after 4 μmol/l salinomycin treatment) and migration capacity in SGC7901/CDDP cells. At the molecular level, we found that the expression of E-cadherin, ZO-1 decreased, whereas the expression of N-cadherin, Vimentin, ZEB-1, and Twist increased in SGC7901/CDDP cells, and that salinomycin potently blocked the EMT by enhancing the expression of E-cadherin, ZO-1 and reducing the expression of N-cadherin, Vimentin, ZEB-1, and Twist in the above MDR cells. In addition, we also found that long noncoding RNA HOTTIP, an oncogenic regulator, was upregulated in SGC7901/CDDP cells, whereas its downregulation could markedly attenuate the EMT, thereby reversing the MDR. Furthermore, our data showed that the salinomycin-elicited MDR-reversion effect was associated closely with suppression of EMT through inhibition of the expression of long noncoding RNA HOTTIP. Collectively, our findings suggest a new underlying mechanism and applicable therapeutic regimen for MDR gastric cancer.