title: sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways.
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.
authors.affiliation: Research Institute, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.|College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Research Institute, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Research Institute, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Park
authors.affiliation: Department of Life Science, Yong In University, Samga-dong, Cheoin-gu, Yongin-si Gyeonggi-do, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Research Institute, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea.
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; C573787:PPP4R3A protein, human; D010749:Phosphoprotein Phosphatases
keywords: anti-angiogenic activity; hypoxic condition; ovarian tumor; sMEK1 tumor suppressor; xenograft model