Abstract 4195: β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through the Cbl-b-EGFR-ERK/Akt signaling pathway

Abstract

Abstract Background/Aims: β-elemene, a Curcuma wenyujin plant extract, has been widely used as an adjuvant therapeutic agent in cancer treatment. The emergence of drug-resistant tumor cells is defined as multidrug resistance (MDR), and is one of the major ways cancer therapy can fail. Our previous study indicated that, compared to chemo-sensitive human gastric cancer cells, drug-resistant cells have a stronger ability for migration. The aim of this study was to explore the anti-metastasis effects and mechanism of β-elemene in multi-drug resistance human gastric cancer cells. Methods: A cell viability assay was used to assess the resistance of adriamycin-resistant human gastric cancer SGC7901 cells (SGC7901/ADR) and the cytotoxic effects of β-elemene on SGC7901/ADR cells. A wound healing assay and transwell assay were used to explore the anti-metastasis effects of β-elemene. Human matrix metalloproteinase (MMP) antibody array and Western blot analysis were used to explore the potential mechanism. A murine tumor metastasis assay was used to confirm the anti-metastasis effects in vivo. Immunohistochemistry analysis was performed to examine the expressions of related proteins in xenograft tumors. Results: At sub-lethal concentrations (1 μg/ml and 5 μg/ml), β-elemene significantly inhibited cell migration and invasion of SGC7901/ADR cells. The human MMP antibody array indicated that β-elemene could regulate almost all proteins of the MMP family, and changes of MMP-2 and MMP-9 were the most obvious. Western blotting showed an increase of E-cadherin and decrease of vimentin in β-elemene-treated cells. Downregulation of transcription factor ZEB1 and ZEB2 was also detected. Treatment of SGC7901/ADR cells with β-elemene led to downregulation of Akt, ERK, and EGFR phosphorylation, and significant upregulation of the E3 ubiquitin ligase, Cbl-b. Changes of these proteins were confirmed in xenograft tumors. Hematoxylin and eosin staining showed significantly decreased numbers of metastatic tumor colonies in the lungs of nude mice injected with SGC7901/ADR cells and β-elemene compared with those only injected with SGC7901/ADR cells. Conclusions: The results strongly suggest that β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells in vitro and in vivo by regulating the Cbl-b-EGFR-ERK/Akt signaling pathway. β-elemene may be a promising treatment for multidrug resistant human gastric cancer. Citation Format: Ruoxi Yu, Mingming Deng, Huicong Song, Dan Zou, Ling Xu, Xiujuan Qu, Yunpeng Liu, Yuee Teng, Xuejun Hu, Ye Zhang. β-elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through the Cbl-b-EGFR-ERK/Akt signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4195.