Abstract
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.
Highlights
Angiogenesis is complex and involves multiple processes, such as tumor growth and metastasis, that are regulated by various pro- and anti-angiogenic factors, including angiogenic proteins, apoptotic regulators, and hormone metabolites
We investigated the interaction between endogenous sMEK1 and vascular endothelial growth factor receptor 2 (VEGFR-2)
It may be suggested that hypoxia significantly promoted the levels of Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression, whereas sMEK1 suppressed their activation
Summary
Angiogenesis is complex and involves multiple processes, such as tumor growth and metastasis, that are regulated by various pro- and anti-angiogenic factors, including angiogenic proteins, apoptotic regulators, and hormone metabolites. VEGF-A binds directly to and activates three receptor tyrosine kinases (RTK): VEGFR-1 (Flt-1), -2 (KDR/Flk-1), and -3 (Flt-4). These receptors control pathological as well as physiological angiogenesis [11, 12]. After binding to VEGF receptors on the surface of endothelial cells, VEGF activates signaling pathways, including PI3K/Akt/mTOR, which subsequently activates endothelial cell recruitment and proliferation [13,14,15,16]. VEGFR-2 has potent tyrosine kinase activity and functions as the major signal transducer in tumor angiogenesis, which involves vascular cell proliferation, migration, and invasion [17,18,19]. Flk-1-deficient mice revealed that Flk-1 is essential for the development of www.impactjournals.com/oncotarget hematopoietic stem cells in embryos, but not for the function of hematopoietic stem cells in adult mouse bone marrow [21]
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