beta-Elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through miR-1323/Cbl-b/EGFR pathway

Background: beta-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of beta-Elemene on MDR cancer cells remain unknown. Purpose: In this study, we posit the hypothesis that beta-elemene possesses antimetastatic effects on MDR cancer cells. Methods: Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of beta-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of beta-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of beta-Elemene. Results: In this study, we found that beta-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that beta-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that beta-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that beta-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after beta-Elemene treatment. Conclusion: Our results suggested that beta-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.