PMID- 26555156 OWN - NLM STAT- MEDLINE DCOM- 20161017 LR - 20211203 IS - 1791-2431 (Electronic) IS - 1021-335X (Linking) VI - 35 IP - 2 DP - 2016 Feb TI - MARCKSL1 exhibits anti-angiogenic effects through suppression of VEGFR-2-dependent Akt/PDK-1/mTOR phosphorylation. PG - 1041-8 LID - 10.3892/or.2015.4408 [doi] AB - 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 1alpha (HIF-1alpha) 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 3beta (GSK-3beta) 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. FAU - Kim, Boh-Ram AU - Kim BR AD - Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea. FAU - Lee, Seung-Hoon AU - Lee SH AD - Department of Life Science, Yong In University, Cheoin-gu, Yongin-si, Gyeonggi‑do 449‑714, Republic of Korea. FAU - Park, Mi-Sun AU - Park MS AD - Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea. FAU - Seo, Seung-Hee AU - Seo SH AD - Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea. FAU - Park, Young-Min AU - Park YM AD - Department of Biological Sciences, Sung Kyun Kwan University, Jangan-gu, Suwon‑si, Gyeonggi‑do 440‑746, Republic of Korea. FAU - Kwon, Young-Joo AU - Kwon YJ AD - College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea. FAU - Rho, Seung-Bae AU - Rho SB AD - Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410‑769, Republic of Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151110 PL - Greece TA - Oncol Rep JT - Oncology reports JID - 9422756 RN - 0 (Calmodulin-Binding Proteins) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (MARCKSL1 protein, human) RN - 0 (Membrane Proteins) RN - 0 (Microfilament Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (KDR protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (GSK3B protein, human) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Calmodulin-Binding Proteins MH - Cell Line, Tumor MH - Cell Movement MH - Endothelial Cells/*physiology MH - Female MH - Glycogen Synthase Kinase 3/biosynthesis/genetics MH - Glycogen Synthase Kinase 3 beta MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/genetics MH - Membrane Proteins/genetics/*physiology MH - Microfilament Proteins MH - Neoplasm Proteins/*antagonists & inhibitors/genetics/physiology MH - Neovascularization, Pathologic/*physiopathology MH - Ovarian Neoplasms/pathology MH - Phosphorylation/physiology MH - Protein Processing, Post-Translational/*physiology MH - Protein Serine-Threonine Kinases/antagonists & inhibitors MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors MH - Pyruvate Dehydrogenase Acetyl-Transferring Kinase MH - Recombinant Fusion Proteins/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/biosynthesis/genetics MH - Signal Transduction/*physiology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Transfection MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/biosynthesis/genetics MH - Two-Hybrid System Techniques MH - Vascular Endothelial Growth Factor Receptor-2/*antagonists & inhibitors EDAT- 2015/11/12 06:00 MHDA- 2016/10/19 06:00 CRDT- 2015/11/12 06:00 PHST- 2015/06/30 00:00 [received] PHST- 2015/08/10 00:00 [accepted] PHST- 2015/11/12 06:00 [entrez] PHST- 2015/11/12 06:00 [pubmed] PHST- 2016/10/19 06:00 [medline] AID - 10.3892/or.2015.4408 [doi] PST - ppublish SO - Oncol Rep. 2016 Feb;35(2):1041-8. doi: 10.3892/or.2015.4408. Epub 2015 Nov 10.