Abstract
Abstract Met is a receptor tyrosine kinase that plays a role in regulating numerous biological functions including mitogenesis, motogenesis, migration, invasion, and eventual metastasis. Met is activated by its natural ligand the hepatocyte growth factor (HGF). It is now well-established that aberrant Met signaling is associated with aggressive cancer phenotypes characterized by highly invasive and metastatic growth. γ-Tocotrienol, a member of the vitamin E family of compounds, displays potent antiproliferative and apoptotic activity against tumor cells. Previous studies have shown that γ-tocotrienol inhibits EGF-dependent growth of +SA murine mammary epithelial cells by suppressing ErbB3 receptor activity and subsequent reduction in the PI3K/Akt signaling. Initial studies have shown that combined treatment with relatively low doses of γ-tocotrienol and the tyrosine kinase inhibitors erlotinib or gefitinib significantly inhibited +SA mammary cell growth. Therefore, the goal of the present study was to investigate the effects of γ-tocotrienol treatment on the Met expression and activation in +SA mammary epithelial tumor cells and to evaluate the effect of combination treatment of γ-tocotrienol and the novel Met inhibitor SU11274. In these experiments, neoplastic +SA mammary epithelial cells were maintained in serum-free defined media containing 10 ng/mL of HGF as the mitogen. Cell culturing studies measuring cell viability were determined by the colorimetric MTT assay, whereas protein expression was determined by Western blotting. Immunofluorescent staining was used to determine treatment effects on Met receptors level and activation. Results showed that treatment with γ-tocotrienol or SU11274, significantly inhibited HGF-dependent proliferation of neoplastic +SA cells in a dose-responsive manner. Western blot analysis showed that treatment with a growth inhibitory dose of γ-tocotrienol (4 μM) caused a large relative reduction in total Met receptor levels, and a corresponding reduction in HGF-induced Met autophosphorylation in +SA mammary tumor cells. In contrast, similar treatment with growth inhibiting doses of SU11274 (5.5 μM) inhibited HGF-induced Met autophosphorylation, but had no effect on total Met levels. Combined treatment with subeffective doses of γ-tocotrienol (2 μM) and SU11274 (3 μM) resulted in a significant inhibition of +SA cell growth as compared to treatment of individual agents alone, and this effect was found to be cytostatic, not cytotoxic. These findings show for the first time the inhibitory effects of γ-tocotrienol on Met expression and activation, and strongly suggest that γ-tocotrienol treatment may provide significant health benefit in the prevention and/or treatment of breast cancer in women with deregulated HGF/Met signaling. This study was supported by a grant from First Tech International Ltd., and the Malaysian Palm Oil Council. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1088. doi:1538-7445.AM2012-1088
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