Abstract
Dysregulation of the Hepatocyte growth factor (HGF)/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis. (-)-Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (-)-oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (-)-oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (-)-oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (-)-oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (-)-oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.
Highlights
About 1 in 8 (12%) women in the US will develop invasive breast cancer during their lifetime [1]
Figure 4. (-)-Oleocanthal treatment caused a dose-dependent suppression of Hepatocyte growth factor (HGF)-induced mammary tumor cell migration and invasion and breast tumor kinase (Brk)/paxillin/Rac1 pathway signaling. (A) Wound healing assay
Right panel represents photomicrographs of cells invading the basement membrane and 15 mM (-)-oleocanthal treatment blocked the invasion of MDA-MB-231 cells. (C) Western blot analysis showing (-)-oleocanthal treatment effects on Brk/Paxillin/Rac1 pathway signaling after 72 h treatment in MDA-MB-231 cancer cells
Summary
About 1 in 8 (12%) women in the US will develop invasive breast cancer during their lifetime [1]. Hepatocyte growth factor (HGF) binds to the extracellular domain of c-Met with high affinity and induces receptor dimerization with consecutive triggering of c-Met tyrosine kinase activity [4]. This is followed by recruitment and phosphorylation of multiple adaptor proteins as well as activation of signaling molecules such as phosphoinositide-3kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), breast tumor kinase (Brk) and phospholipase C-c (PLC- c) pathways [4,5,6,7]. There is a mounting evidence for the involvement of chronic or dysregulated activation of c-Met receptor tyrosine kinase and its ligand HGF in multiple types of tumor cells leading to enhancing cell growth, angiogenesis, and survival. Targeting c-Met activity with small molecule inhibitors of the HGF/c-Met axis can be considered a promising approach for cancer treatment and prevention [4,5,6,8]
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