BackgroundTrastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent therapeutic resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. In this study, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 reversed this resistance.MethodsThe effect of trastuzumab and glycolysis inhibitor combination on cell viability, apoptosis, and cell metabolism was investigated in vitro using established trastuzumab-resistant GC cell lines. We assessed the impact of trastuzumab combined with oxamate on tumor growth and metabolism in an established xenograft model of HER2-positive GC cell lines.ResultsHere, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 in trastuzumab-resistant cells reversed this resistance. Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effects of MACC1 on resistance and glycolysis were diminished. Our findings indicated that MACC1 promoted the Warburg effect mainly through the PI3K/AKT signaling pathway, which further enhanced GC cells trastuzumab resistance.ConclusionsOur results indicate that co-targeting of HER2 and the Warburg effect reversed trastuzumab resistance in vitro and in vivo, suggesting that the combination might overcome trastuzumab resistance in MACC1-overexpressed, HER2-positive GC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0302-1) contains supplementary material, which is available to authorized users.
Transforming growth factor-β (TGF-β) promotes cancer metastasis via the epithelial-mesenchymal transition (EMT) but the underlying mechanisms in nasopharyngeal carcinoma (NPC) remain unclear. Flotillin-2 (Flot2), a specialized lipid raft domain in cellular membrane, was reported to promote cancer metastasis. Recently, in neuropathy, it was also suggested that Flot2 was involved in Src activation, which is known as the downstream signal of TGF-β. Therefore, we intended to find out the relationship between Flot2 and TGF-β in the process of nasopharyngeal carcinoma (NPC) metastasis. In this study, we found that Flot2 expression level positively correlated with the cancer stage in NPC tissues. Elevated Flot2 in tumor tissue was an independent prognostic marker, and higher Flot2 expression level showed shorter overall survival time in 181 NPC patients. In NPC cells, silencing Flot2 reversed the metastatic effect induced by TGF-β. Moreover, TGF-β-induced Src phosphorylation was significantly inhibited by Flot2 knocking down. As the consequence of Flot2 inhibition, the expression of the epithelial biomarker E-cadherin was upregulated, while the mesenchymal marker vimentin and signaling transducer β-catenin was suppressed. In conclusions, Flot2 is an indispensable member for TGF-β signaling, which is essential for the EMT process in NPC metastasis. Suppressing Flot2 may be a novel way against TGF-β-induced EMT.
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