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

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 beta-arrestin-2 (beta arr2) depletion promotes CXCR2-mediated cellular signaling, including angiogenesis and excisional wound closure. This study was designed to investigate the role of beta arr2 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 beta arr2-deficient mice (beta arr2(-/-)) and control littermates (beta arr2(+/+)) were used. beta arr2(-/-) mice exhibited a significant increase in Lewis lung cancer tumor growth and metastasis relative to beta arr2(+/+) 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-kappa B activity was also enhanced in beta arr2(-/-) mice, whereas hypoxia-inducible factor-la expression was decreased. Inhibition of CXCR2 or NF-kappa B reduced tumor growth in both beta arr2(-/-) and beta arr2(+/+) mice. NF-kappa B inhibition also decreased ELR+ chemokines and vascular endothelial growth factor expression. Altogether, the data suggest that beta arr2 modulates tumorigenesis by regulating inflammation and angiogenesis through activation of CXCR2 and NF-kappa B.