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* Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Durham, NC 27707; and
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Virginia Health System, Charlottesville, VA 22908
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 tumor-infiltrating 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-
B activity was also enhanced in βarr2–/– mice, whereas hypoxia-inducible factor-1
expression was decreased. Inhibition of CXCR2 or NF-B reduced tumor growth in both βarr2–/– and βarr2+/+ mice. NF-B 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-B.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI38910 and 056-CA92077, the National Center on Minority Health and Health Disparities (P20 MD00175), and the U.S. Army Medical Research and Materiel Command (07-1-0418).
2 Address correspondence and reprint requests to Dr. Ricardo M. Richardson, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707. E-mail address: mrrichardson{at}nccu.edu
3 Abbreviations used in this paper: GPCR, G protein-coupled receptor; βarr2, β-arrestin-2; CXCL8, IL-8; CXCR2, IL-8 receptor B; ELR, Glu-Leu-Arg; HIF-1, hypoxia-inducible factor-1; KC or CXCL1, keratinocyte-derived chemokine; LLC, Lewis lung cancer; MIP-2 or CXCL2, macrophage inflammatory protein-2; RBL, rat basophilic leukemia; RIPA, radioimmune precipitation assay; VEGF, vascular endothelial growth factor.
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