Depletion of β-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer

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 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-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.