Abstract 4458: Antiproliferative effects of γ-tocotrienol are mediated by suppression in the activation of Met tyrosine kinase receptors in neoplastic +SA mammary epithelial cells

Abstract

Abstract γ-Tocotrienol, a member of vitamin E family of compounds, displays potent anticancer activity against breast and other types of cancers. Previous studies have shown that the antiproliferative effects of γ-tocotrienol are associated with the suppression in the epidermal growth factor (EGF)-dependent phosphatidylinositol-3-kinase (PI3K)-dependent kinase-1 (PDK-1) and Akt phosphorylation in neoplastic +SA mammary epithelial cells. Also, studies showed that γ-tocotrienol treatment had no direct effect on Akt activity and did not alter the relative intracellular levels of PI3K, indicating that γ-tocotrienol might act upstream of the PI3K/PDK-1/Akt pathways at the level of membrane tyrosine kinase receptors in +SA mammary tumor cells. Since aberrant activation of the Met tyrosine kinase receptors is observed in various types of cancers and is associated with poor prognosis, studies were conducted to determine the effect of γ-tocotrienol on EGF and hepatocyte growth factor (HGF)-dependent activation of Met tyrosine kinase receptors in +SA mammary tumor cells. Treatment with serum-free media containing various doses of EGF (1-10 ng/ml) or HGF (1-10 ng/ml) significantly increased the growth of +SA mammary tumor cells as compared to serum-free control group over a 3-day culture period. Stimulation of +SA cells with EGF (10 ng/ml) or HGF (10 ng/ml) resulted in the activation of Met tyrosine kinase receptors. Treatment with Met tyrosine kinase inhibitor, SU11274 (5.5 μM) or γ-tocotrienol (4 μM) inhibited the EGF or HGF-dependent growth and activation of Met receptors in +SA mammary tumor cells after a 3-day culture period. Also, knockdown of Met receptors using Met specific siRNA decreased the expression of Met receptors and significantly inhibited the EGF or HGF-dependent growth of +SA cells. Additional studies showed that when +SA cells were simultaneously exposed to EGF (10 ng/ml) and HGF (10 ng/ml), the growth inhibitory effects of γ-tocotrienol (4 μM) and SU11274 (5.5 μM) were significantly reversed, associated with the activation of Met receptors. However, combined treatment with low doses of γ-tocotrienol (2 μM) and SU11274 (3 μM) inhibited the EGF and/or HGF-dependent growth of neoplastic +SA mammary epithelial cells. These results 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. Supported by grants from NIH (CA86833) and First Tech International Ltd. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4458.