Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis

Chandra Shekhar Boosani, Arjuna P. Mannam, Dominic E Cosgrove, Rita Silva, Kairbaan M. Hodivala-Dilke, Venkateshwar G. Keshamouni, Akulapalli Sudhakar

Research output: Contribution to journalArticle

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Abstract

Human α3 chain, a noncollagenous domain of type IV collagen [α3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of α3(IV)NC1 to αVβ3 and α3β1 integrins. α3(IV)NC1 binds αVβ3 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 α3β1 and αVβ3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on α3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by α3(IV)NC1 in endothelial cells, only α3β1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of α3(IV)NC1 to α3β1 integrin leads to inhibition of COX-2-mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IκBα/NFκB axis, and is independent of αVβ3 integrin. Furthermore, β3 integrin-null endothelial cells, when treated with α3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in α3 integrin-null endothelial cells, indicating that regulation of COX-2 by α3(IV)NC1 is mediated by integrin α3β1. Our in vitro and in vivo findings demonstrate that α3β1 integrin is critical for α3(IV)NC1-mediated inhibition of COX-2-dependent angiogenic signaling and inhibition of tumor progression.

Original languageEnglish (US)
Pages (from-to)1168-1177
Number of pages10
JournalBlood
Volume110
Issue number4
DOIs
StatePublished - Aug 15 2007

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Cyclooxygenase 2
Integrins
Tumors
Neoplasms
Endothelial cells
Endothelial Cells
Null Lymphocytes
Phosphatidylinositol 3-Kinase
Focal Adhesion Protein-Tyrosine Kinases
Collagen Type III
Collagen Type IV
Angiogenesis Inducing Agents
Fibroblast Growth Factor 2
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Boosani, C. S., Mannam, A. P., Cosgrove, D. E., Silva, R., Hodivala-Dilke, K. M., Keshamouni, V. G., & Sudhakar, A. (2007). Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis. Blood, 110(4), 1168-1177. https://doi.org/10.1182/blood-2007-01-066282

Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis. / Boosani, Chandra Shekhar; Mannam, Arjuna P.; Cosgrove, Dominic E; Silva, Rita; Hodivala-Dilke, Kairbaan M.; Keshamouni, Venkateshwar G.; Sudhakar, Akulapalli.

In: Blood, Vol. 110, No. 4, 15.08.2007, p. 1168-1177.

Research output: Contribution to journalArticle

Boosani, CS, Mannam, AP, Cosgrove, DE, Silva, R, Hodivala-Dilke, KM, Keshamouni, VG & Sudhakar, A 2007, 'Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis', Blood, vol. 110, no. 4, pp. 1168-1177. https://doi.org/10.1182/blood-2007-01-066282
Boosani CS, Mannam AP, Cosgrove DE, Silva R, Hodivala-Dilke KM, Keshamouni VG et al. Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis. Blood. 2007 Aug 15;110(4):1168-1177. https://doi.org/10.1182/blood-2007-01-066282
Boosani, Chandra Shekhar ; Mannam, Arjuna P. ; Cosgrove, Dominic E ; Silva, Rita ; Hodivala-Dilke, Kairbaan M. ; Keshamouni, Venkateshwar G. ; Sudhakar, Akulapalli. / Regulation of COX-2-mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis. In: Blood. 2007 ; Vol. 110, No. 4. pp. 1168-1177.
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abstract = "Human α3 chain, a noncollagenous domain of type IV collagen [α3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of α3(IV)NC1 to αVβ3 and α3β1 integrins. α3(IV)NC1 binds αVβ3 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 α3β1 and αVβ3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on α3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by α3(IV)NC1 in endothelial cells, only α3β1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of α3(IV)NC1 to α3β1 integrin leads to inhibition of COX-2-mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IκBα/NFκB axis, and is independent of αVβ3 integrin. Furthermore, β3 integrin-null endothelial cells, when treated with α3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in α3 integrin-null endothelial cells, indicating that regulation of COX-2 by α3(IV)NC1 is mediated by integrin α3β1. Our in vitro and in vivo findings demonstrate that α3β1 integrin is critical for α3(IV)NC1-mediated inhibition of COX-2-dependent angiogenic signaling and inhibition of tumor progression.",
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AU - Silva, Rita

AU - Hodivala-Dilke, Kairbaan M.

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AB - Human α3 chain, a noncollagenous domain of type IV collagen [α3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of α3(IV)NC1 to αVβ3 and α3β1 integrins. α3(IV)NC1 binds αVβ3 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 α3β1 and αVβ3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on α3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by α3(IV)NC1 in endothelial cells, only α3β1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of α3(IV)NC1 to α3β1 integrin leads to inhibition of COX-2-mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IκBα/NFκB axis, and is independent of αVβ3 integrin. Furthermore, β3 integrin-null endothelial cells, when treated with α3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in α3 integrin-null endothelial cells, indicating that regulation of COX-2 by α3(IV)NC1 is mediated by integrin α3β1. Our in vitro and in vivo findings demonstrate that α3β1 integrin is critical for α3(IV)NC1-mediated inhibition of COX-2-dependent angiogenic signaling and inhibition of tumor progression.

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