Regulation of COX-2 mediated signaling by alpha3 type IV noncollagenous domain in tumor angiogenesis
Authors: Arjuna P Mannam
Chandra Shekhar Boosani
Venkateshwar G Keshamouni
Dominic Cosgrove
Rita Silva
Kairbaan M Hodivala-Dilke
Akulapalli Sudhakar
Journal: Blood (2007)
Discipline: CLINICAL MEDICINE
Keywords: alpha3(IV)NC1; angiogenesis; tumor growth; integrins; tube formation
Affiliations: Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE;, Department of Neurology, University of Connecticut School of Medicine, Hartford Hospital;, Gene Expression Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE;, Cancer Research UK, Cell Adhesion and Disease Laboratory, Richard Dimbleby Department of Cancer Research, St Thomas' Hospital, London, United Kingdom;, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor;, Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE;, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha

Abstract:  Human alpha3 chain, a noncollagenous domain of type IV collagen [alpha3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of alpha3(IV)NC1 to alphaVbeta3 and alpha3beta1 integrins. alpha3(IV)NC1 binds alphaVbeta3 integrin, leading to translation inhibition by inhibiting focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathways. In the present study, we evaluated the role of alpha3beta1 and alphaVbeta3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on alpha3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by alpha3(IV)NC1 in endothelial cells, only alpha3beta1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of alpha3(IV)NC1 to alpha3beta1 integrin leads to inhibition of COX-2-mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IkappaBalpha/NFkappaB axis, and is independent of alphaVbeta3 integrin. Furthermore, beta3 integrin-null endothelial cells, when treated with alpha3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in alpha3 integrin-null endothelial cells, indicating that regulation of COX-2 by alpha3(IV)NC1 is mediated by integrin alpha3beta1. Our in vitro and in vivo findings demonstrate that alpha3beta1 integrin is critical for alpha3(IV)NC1-mediated inhibition of COX-2-dependent angiogenic signaling and inhibition of tumor progression. 

Retracted: No

PubPeer comments:
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 Figure 1C continued. https: imgur.com ai1ETfh , 
 It should also be pointed out that Figure 1 in this paper is derived from Figure 1 in an earlier publication by this group: Sudhakar et al. J. Clin. Invest.u2002115:2801u20132810u2002(2005) The assays are described for HUVECs in that paper, and MLECs in this one. I have highlighted one re-use.  , 
 https: grants.nih.gov grants guide notice-files NOT-OD-20-028.html Odd that the other authors donu2019t bother to address this paper. ,