Abstract
Mesenchymal epithelial transition factor receptor (Met) is a receptor tyrosine kinase that plays a critical role in promoting cancer cell malignant progression. Met is activated by its ligand hepatocyte growth factor (HGF). HGF-dependent Met activation plays an important role in stimulating epithelial-mesenchymal transition (EMT) in tumor cells, resulting in increased tumor cell proliferation, survival, motility, angiogenesis, invasion, and metastasis. The HGF/Met axis has thus attracted great interest as a potential target in the development of novel cancer therapies. In an effort to suppress tumor cell malignant progression, efforts have been made to develop agents capable of inhibiting inhibit Met-induced EMT, including specific Met tyrosine kinase inhibitors, HGF antagonists that interfere with HGF binding to Met, and antibodies that prevent Met activation and/or dimerization. Tocotrienols, a subgroup within the vitamin E family of compounds, display potent anticancer activity that results, at least in part, from inhibition of HGF-dependent Met activation and signaling. The present review will provide a brief summary of the increasing importance of the HGF/Met axis as an attractive target for cancer chemotherapy and the role of tocotrienols in suppressing Met activation, signaling and HGF-induced EMT in breast cancer cells. Evidence provided suggests that γ-tocotrienol therapy may afford significant benefit in the treatment of breast cancers characterized by Met dysregulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-014-0030-5) contains supplementary material, which is available to authorized users.
Highlights
Traditional cancer chemotherapeutic agents typically exhibit non-selective activity and often produce low response rates and severe toxic side effects in patients [1]
These findings provide evidence that γ-tocotrienol inhibits hepatocyte growth factor (HGF)-dependent mesenchymal epithelial transition factor (Met) activation and signaling and causes reversal of epithelial-mesenchymal transition (EMT)
Recent studies show that during hypoxic conditions, natural and semisynthetic derivatives of tocotrienols inhibit mammary tumor cell expression of hypoxiainducible factor-1 (HIF-1), Protein kinase B (Akt)/Mammalian target of rapamycin (mTOR) activity and vascular endothelial growth factor (VEGF) production in vitro and in vivo [63]. These findings suggest that tocotrienol treatment can act to suppress the compensatory mechanisms that promote tumor growth and survival during hypoxic conditions, possibly through the inhibition of HGF/Met activation, additional studies are required to establish a direct relationship
Summary
Met is implicated in malignant progression. Excessive or unregulated tumor cell Met activity is associated with poor patient prognosis owing to aggressive malignant phenotype typified by enhanced angiogenesis, invasion and metastasis [5,6,7,8]. Since combined treatment with low dose of γ-tocotrienol and SU11274 has profound inhibitory effects on tumor cell growth and HGF-dependent Met activation and signaling, additional studies aimed to determine effects of these agents on breast cancer cell epithelial and mesenchymal cell marker expression. Taken together, these findings provide evidence that γ-tocotrienol inhibits HGF-dependent Met activation and signaling and causes reversal of EMT. Recent studies show that during hypoxic conditions, natural and semisynthetic derivatives of tocotrienols inhibit mammary tumor cell expression of HIF-1, Akt/mTOR activity and VEGF production in vitro and in vivo [63] These findings suggest that tocotrienol treatment can act to suppress the compensatory mechanisms that promote tumor growth and survival during hypoxic conditions, possibly through the inhibition of HGF/Met activation, additional studies are required to establish a direct relationship.
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