γ-Tocotrienol inhibits HGF-dependent mitogenesis and Met activation in highly malignant mammary tumour cells

Objectives: Aberrant Met signalling is associated with aggressive cancer cell phenotypes. gamma-tocotrienol displays potent anti-cancer activity that is associated with suppression of HER/ErbB receptor signalling. Experiments were conducted to investigate the effects of gamma-tocotrienol treatment on HGF-dependent +SA mammary tumour cell proliferation, upon Met activation. Materials and methods: The +SA cells were maintained in serum-free defined media containing 10 ng/ml HGF as the mitogen. Cell viability was determined using the MTT assay, western blot analysis was used to measure protein expression, and Met expression and activation were determined using immunofluorescent staining. Results and conclusions: Treatment with gamma-tocotrienol or Met inhibitor, SU11274, significantly inhibited HGF-dependent +SA cell replication in a dose-responsive manner. Treatment with 4 mu M gamma-tocotrienol reduced both total Met levels and HGF-induced Met autophosphorylation. In contrast, similar treatment with 5.5 mu M SU11274 inhibited HGF-induced Met autophosphorylation, but had no effect on total Met levels. Combined treatment with subeffective doses of gamma-tocotrienol (2 lM) and SU11274 (3 lM) resulted in significant inhibition of +SA cell expansion compared to treatment with individual agents alone. These findings show, for the first time, the inhibitory effects of gamma-tocotrienol on Met expression and activation, and strongly suggest that gamma-tocotrienol treatment may provide significant health benefits in prevention and/or treatment of breast cancer, in women with deregulated HGF/Met signalling.