β-Elemene Inhibits the Metastasis of Multidrug-Resistant Gastric Cancer Cell Through miR-1323/Cbl-b/EGFR Pathway

Abstract

β-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 antimetastatic effects of β-Elemene on MDR cancer cells remain unknown. In this study, we found that β-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that β-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that β-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that β-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. These results suggested that β-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis. Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81472193, 81270036, 30901736), the Plan to Focus on Research and Development from Science and Technology project of Liaoning Province (No. 2017225029), Science and Technology Plan Project of Shenyang City (No. 18-014-4-11), and Fund for Scientific Research of The First Hospital of China Medical University (No. FHCMU- FSR). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All of the animal experiments conformed to the Guide for Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of China Medical University. β-Elemene is an antitumor drug derived from an herbal Chinese medicine and has been approved in China for clinical use to treat many tumor types (27, 28).