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

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 anti-metastatic effects of β-Elemene on MDR cancer cells remain unknown. In this study, we posit the hypothesis that β-elemene possesses antimetastatic effects on MDR cancer cells. Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of β-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of β-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 β-Elemene. 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. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after β-Elemene treatment. Our results suggested that β-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.

Deng M ，Liu B ，Song H ，Yu R ，Zou D ，Chen Y ，Ma Y ，Lv F ，Xu L ，Zhang Z ，Lv Q ，Yang X ，Che X ，Qu X ，Liu Y ，Zhang Y ，Hu X ... -  《-》

The role of E3 ubiquitin ligase Cbl proteins in β-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells.

Zhang Y ，Mu XD ，Li EZ ，Luo Y ，Song N ，Qu XJ ，Hu XJ ，Liu YP ... -  《-》

E3 Ubiquitin Ligase Cbl-b Prevents Tumor Metastasis by Maintaining the Epithelial Phenotype in Multiple Drug-Resistant Gastric and Breast Cancer Cells.

Multiple drug resistance (MDR) and metastasis are two major factors that contribute to the failure of cancer treatment. However, the relationship between MDR and metastasis has not been characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is not well known. In the present study, we found that MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. In MDR gastric adenocarcinoma tissues, gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=.016) and lymph node metastasis (P=.007). Moreover, overexpression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b overexpression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR-ERK/Akt-miR-200c-ZEB1 axis. However, further overexpression of EGFR on a background of Cbl-b overexpression restored both the mesenchymal phenotype and cell migration capacity of MDR gastric and breast cancer cells. These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells.

Xu L ，Zhang Y ，Qu X ，Che X ，Guo T ，Cai Y ，Li A ，Li D ，Li C ，Wen T ，Fan Y ，Hou K ，Ma Y ，Hu X ，Liu Y ... -  《NEOPLASIA》

Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells.

Li H ，Xu L ，Li C ，Zhao L ，Ma Y ，Zheng H ，Li Z ，Zhang Y ，Wang R ，Liu Y ，Qu X ... -  《Molecular Cancer》

β-Elemene inhibits peritoneal metastasis of gastric cancer cells by modulating FAK/Claudin-1 signaling.

Peritoneal metastasis is common in advanced gastric cancer patients and is typically associated with a worse prognosis. β-Elemene is a natural compound that can be isolated from the Curcuma wenyujin plant and has been widely used in China to treat a variety of cancers. However, the anti-metastatic impacts of β-elemene on gastric cancer remain unknown. In our study, we found that β-elemene significantly inhibited the migration and invasive capacity of gastric cells in vitro and inhibited the capacity of gastric cancer cells to peritoneally diffuse and metastasize in vivo. Mechanistically, we demonstrated that the anti-metastatic effects of β-elemene were exerted by downregulating the expression of Claudin-1. Furthermore, β-elemene was found to inhibit the metastatic capacity of cells by downregulating FAK phosphorylation, which regulated Claudin-1. Overall, our result revealed that β-elemene inhibited peritoneal metastases from gastric cancer by modulating the FAK/Claudin-1 pathway.

Deng M ，Zhang Y ，Liu B ，Chen Y ，Song H ，Yu R ，Che X ，Qu X ，Liu Y ，Hu X ，Xu X ... -  《-》