title: Ephrin-A1 is up-regulated by hypoxia in cancer cells and promotes angiogenesis of HUVECs through a coordinated cross-talk with eNOS.
abstract: Hypoxia, ephrin-A1 and endothelial nitric oxide synthase (eNOS) have been proved to play critical roles in tumor angiogenesis. However, how ephrin-A1 is regulated by hypoxia and whether ephrin-A1 cooperates with eNOS in modulation of angiogenesis remain to be addressed in details. Here we demonstrated that both ephrin-A1 in squamous cell carcinoma cells (SCC-9) and especially soluble ephrin-A1 in the supernatants were up-regulated under hypoxic condition. An increased nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) was observed in ephrin-A1-induced angiogenesis which was reversed after co-culture with eNOS specific inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME). Western blot analysis confirmed that both phosphorylation of Akt(Ser473) and eNOS(Ser1177) were up-regulated in ephrin-A1-stimulated HUVECs, with the total eNOS expression unchanged. The specific inhibitor of phosphatidylinositol 3-kinase (PI3K), LY294002, significantly down-regulated ephrin-A1-induced expression of phosphorylated Akt(Ser473) as well as phosphorylation of eNOS(Ser1177). These results revealed a possible novel mechanism whereby ephrin-A1 is regulated in tumor microenvironment and promotes angiogenesis through a coordinated cross-talk with PI3K/Akt-dependent eNOS activation which may relate to normal vascular development and tumor neovascularization.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhao
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.forename: Zheng-Jun
authors.initials: ZJ
authors.lastname: Shang
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036382:Ephrin-A1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D036382:Ephrin-A1; D009025:Morpholines; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496314:NOS3 protein, human
references.citation: Apoptosis. 2000 Oct;5(4):323-8
references.pmid: 11227213
references.citation: Cardiovasc Res. 2013 Jun 1;98(3):437-48
references.pmid: 23408345
references.citation: J Cell Sci. 2004 Apr 15;117(Pt 10):2037-49
references.pmid: 15054110
references.citation: J Clin Invest. 1997 Dec 15;100(12):3131-9
references.pmid: 9399960
references.citation: Trends Mol Med. 2011 Jul;17(7):347-62
references.pmid: 21481637
references.citation: Nat Rev Cancer. 2006 Jul;6(7):521-34
references.pmid: 16794635
references.citation: Oncogene. 2002 Oct 10;21(46):7011-26
references.pmid: 12370823
references.citation: Trends Biochem Sci. 1997 Jul;22(7):267-72
references.pmid: 9255069
references.citation: Clin Cancer Res. 2010 Sep 15;16(18):4636-46
references.pmid: 20823141
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2604-9
references.pmid: 11226286
references.citation: Oncogene. 2002 Oct 31;21(50):7690-9
references.pmid: 12400011
references.citation: J Biol Chem. 2001 Apr 27;276(17):13771-7
references.pmid: 11278471
references.citation: Biochem J. 2006 Sep 1;398(2):279-88
references.pmid: 16716148
references.citation: Semin Cell Dev Biol. 2012 Feb;23(1):109-15
references.pmid: 22040911
references.citation: Nature. 1999 Jun 10;399(6736):601-5
references.pmid: 10376603
references.citation: PLoS One. 2012;7(7):e40365
references.pmid: 22808143
references.citation: J Natl Cancer Inst. 1998 Apr 15;90(8):587-96
references.pmid: 9554441
references.citation: Cytokine Growth Factor Rev. 2002 Feb;13(1):75-85
references.pmid: 11750881
references.citation: J Mol Cell Cardiol. 2007 Feb;42(2):271-9
references.pmid: 16839566
references.citation: Mol Cancer Res. 2005 Oct;3(10):541-51
references.pmid: 16254188
references.citation: Cardiovasc Res. 2007 Jul 15;75(2):247-60
references.pmid: 17466957
references.citation: Biomacromolecules. 2011 Jul 11;12(7):2715-22
references.pmid: 21639150
references.citation: Cancer Res. 2004 Aug 1;64(15):5283-90
references.pmid: 15289334
references.citation: Int J Cancer. 2010 Feb 15;126(4):940-9
references.pmid: 19642143
references.citation: Mol Cell Biol. 2012 Aug;32(16):3253-64
references.pmid: 22688511
references.citation: Nat Rev Cancer. 2002 Jan;2(1):38-47
references.pmid: 11902584
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: J Biol Chem. 2007 Jan 26;282(4):2683-94
references.pmid: 17135240
references.citation: Nat Rev Cancer. 2010 Mar;10(3):165-80
references.pmid: 20179713
references.citation: J Biol Chem. 2008 Jul 4;283(27):18926-36
references.pmid: 18434321
references.citation: Oral Oncol. 2008 Dec;44(12):1110-7
references.pmid: 18485799
references.citation: J Cell Sci. 2004 May 15;117(Pt 12):2427-9
references.pmid: 15159447
references.citation: Oncogene. 2008 Dec 11;27(58):7260-73
references.pmid: 18794797
references.citation: Trends Cardiovasc Med. 2005 Jul;15(5):157-62
references.pmid: 16165011
references.citation: Nature. 2002 Mar 21;416(6878):279-80
references.pmid: 11907566
references.citation: Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):167-75
references.pmid: 17707270
references.citation: Cell Signal. 2009 Jun;21(6):906-15
references.pmid: 19385062
references.citation: Cancer Res. 2006 Nov 1;66(21):10315-24
references.pmid: 17079451
references.citation: Science. 1994 Nov 4;266(5186):816-9
references.pmid: 7973638
references.citation: FASEB J. 2005 Oct;19(12):1689-91
references.pmid: 16081502
references.citation: Cell Tissue Res. 2003 Oct;314(1):145-55
references.pmid: 12898211