Met is a receptor tyrosine kinase. Dysregulation of Met signaling is associated with aggressive cancer phenotypes characterized by highly invasive and metastatic growth. Low dose treatment of γ-tocotrienol, a rare form of vitamin E, has previously been shown to inhibit Met receptor activation and mammary tumor cell proliferation when combined with the Met inhibitor, SU11274. Experiments were conducted to determine the intracellular mechanisms involved in mediating the anticancer effects of combined γ- tocotrienol and SU11274 treatment in mammary cancer cell lines. Mouse (+SA) and human (MCF-7, and MDA-MB-231) mammary cancer cell lines, and CL-S1 (mouse) and MCF10A (human) immortalized normal mammary epithelial cell lines were compared. Cell proliferation and survival were determined by MTT assay and Ki-67 staining. Protein expression was determined by Western blotting. Immunofluorescent staining was used to characterize expression and localization of multiple epithelial and mesenchymal markers. Cell migration was determined using the wound healing assay. Combined treatment of subeffective concentrations of γ- tocotrienol and SU11274 resulted in a synergistic growth inhibition in +SA, MCF-7, and MDA-MB-231 cells, but had no effect on CL-S1 and MCF10A viability. Additional studies showed that combined treatment caused a large reduction in phosphorylated-Akt (active) levels and suppressed HGF-induced epithelial-to-mesenchymal transition (EMT) in +SA cells, as indicated by a characteristic increase in epithelial markers E-cadherin, membrane-bound β- catenin, and cytokeratins 8/18, and a corresponding decrease in mesenchymal marker vimentin expression, as compared to vehicle-treated controls.
Combined treatment with γ-tocotrienol and SU11274 blocked HGF-induced +SA and MDA-MB-231 cell motility. These results demonstrate that the anticancer effects of combined γ-tocotrienol and SU11274 treatment aremediated by a suppression in hepatocyte growth factor (HGF)-induced mitogenic signaling, EMT, and cell motility, and suggest that the use of these agents may provide significant benefits in the treatment of breast cancers characterized by aberrant Met activity. This work was supported, in part, by grants from First Tec International Ltd. (Hong Kong), the Malaysian Palm Oil Council (MPOC), and the Louisiana Cancer Foundation.
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