title: MARCKSL1 exhibits anti-angiogenic effects through suppression of VEGFR-2-dependent Akt/PDK-1/mTOR phosphorylation.
abstract: Myristoylated alanine-rich C kinase substrate-like 1 (MARCKSL1) plays a pivotal role in the regulation of apoptosis and has been shown to maintain antitumor and metastasis-suppressive properties. In the present study, we examined the effects of MARCKSL1 as a novel anti-angiogenic agent on the inhibition of angiogenesis-mediated cell migration. MARCKSL1 also reduced vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation, as well as capillary-like tubular structure formation in vitro. MARCKSL1 disrupted phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) in ovarian tumorigenesis. In addition, MARCKSL1 showed potent anti-angiogenic activity and reduced the levels of VEGF and hypoxia-inducible factor 1α (HIF-1α) expression, an essential regulator of angiogenesis. Consistently, MARCKSL1 decreased VEGF‑induced phosphorylation of the PI3K/Akt signaling pathway components, including phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), tuberous sclerosis complex 2 (TSC-2), p70 ribosomal protein S6 kinase (p70S6K), and glycogen synthase kinase 3β (GSK-3β) protein. Collectively, our results provide evidence for the physiological/biological function of an endothelial cell system involved in angiogenesis through suppression of Akt/PDK-1/mTOR phosphorylation by interaction with VEGFR-2.
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea.
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Department of Life Science, Yong In University, Cheoin-gu, Yongin-si, Gyeonggi‑do 449‑714, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Park
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Biological Sciences, Sung Kyun Kwan University, Jangan-gu, Suwon‑si, Gyeonggi‑do 440‑746, Republic of Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Park
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea.
authors.forename: Seung-Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D002148:Calmodulin-Binding Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010051:Ovarian Neoplasms / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D020798:Two-Hybrid System Techniques; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D002148:Calmodulin-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C070177:MARCKSL1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011993:Recombinant Fusion Proteins; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3