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

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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
DOIs
StatePublished - Apr 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Depletion of β-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer'. Together they form a unique fingerprint.

Cite this