Depletion of β-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer

Sandeep K. Raghuwanshi, Mohd W. Nasser, Xiaoxin Chen, Robert M. Strieter, Ricardo M. Richardson

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Abstract

Arrestins are adaptor/scaffold proteins that complex with activated and phosphorylated G protein-coupled receptor to terminate G protein activation and signal transduction. These complexes also mediate downstream signaling, independently of G protein activation. We have previously shown that β-arrestin-2 (βarr2) depletion promotes CXCR2-mediated cellular signaling, including angiogenesis and excisional wound closure. This study was designed to investigate the role of βarr2 in tumorigenesis using a murine model of lung cancer. To that end, heterotopic murine Lewis lung cancer and tail vein metastasis tumor model systems in βarr2-deficient mice (βarr2 -/-) and control littermates (βarr2 +/+) were used. βarr2 -/- mice exhibited a significant increase in Lewis lung cancer tumor growth and metastasis relative to βarr2 +/+ mice. This correlated with decreased number of tumorinfiltrating lymphocytes but with elevated levels of the ELR + chemokines (CXCL1/keratinocyte-derived chemokine and CXCL2/ MIP-2), vascular endothelial growth factor, and microvessel density. NF-κB activity was also enhanced in βarr2 -/- mice, whereas hypoxia-inducible factor-1α expression was decreased. Inhibition of CXCR2 or NF-κB reduced tumor growth in both βarr2 -/- and βarr2 +/+ mice. NF-κB inhibition also decreased ELR + chemokines and vascular endothelial growth factor expression. Altogether, the data suggest that βarr2 modulates tumorigenesis by regulating inflammation and angiogenesis through activation of CXCR2 and NF-κB. The Journal of Immunology,

Original languageEnglish (US)
Pages (from-to)5699-5706
Number of pages8
JournalJournal of Immunology
Volume180
Issue number8
Publication statusPublished - Apr 15 2008

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Raghuwanshi, S. K., Nasser, M. W., Chen, X., Strieter, R. M., & Richardson, R. M. (2008). Depletion of β-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer. Journal of Immunology, 180(8), 5699-5706.