sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways
Copyright policy )sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways
The suppressor of MEK null (sMEK1) protein possesses pro-apoptotic activities. In the current study, we reveal that sMEK1 functions as a novel anti-angiogenic factor by suppressing vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tubular structure in vitro. In addition, sMEK1 inhibited the phosphorylation of the signaling components up- and downstream of Akt, including phospholipase Cγ1 (PLC-γ1), 3-phosphoinositide-dependent protein kinase 1 (PDK1), endothelial nitric oxide synthetase (eNOS), and hypoxia-inducible factor 1 (HIF-1α) during ovarian tumor progression via binding with vascular endothelial growth factor receptor 2 (VEGFR-2). Furthermore, sMEK1 decreased tumor vascularity and inhibited tumor growth in a xenograft human ovarian tumor model. These results supply convincing evidence that sMEK1 controls endothelial cell function and subsequent angiogenesis by suppressing VEGFR-2-mediated PI3K/Akt/eNOS signaling pathway. Taken together, our results clearly suggest that sMEK1 might be a novel anti-angiogenic and anti-tumor agent for use in ovarian tumor.
- National Cancer Center Korea (Republic of)
- National Cancer Center United States
- College of Pharmacy Iraq
- National Cancer Centre Japan
- Ewha Womans University
Ovarian Neoplasms, Mice, Inbred BALB C, Neovascularization, Pathologic, Nitric Oxide Synthase Type III, Blotting, Western, Mice, Nude, Apoptosis, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoenzyme Techniques, Mice, Cell Movement, Human Umbilical Vein Endothelial Cells, Phosphoprotein Phosphatases, Animals, Humans, Immunoprecipitation, Female, Phosphorylation, Cells, Cultured, Cell Proliferation
Ovarian Neoplasms, Mice, Inbred BALB C, Neovascularization, Pathologic, Nitric Oxide Synthase Type III, Blotting, Western, Mice, Nude, Apoptosis, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoenzyme Techniques, Mice, Cell Movement, Human Umbilical Vein Endothelial Cells, Phosphoprotein Phosphatases, Animals, Humans, Immunoprecipitation, Female, Phosphorylation, Cells, Cultured, Cell Proliferation
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