Eintrag weiter verarbeiten
Depletion of β-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer
Gespeichert in:
Zeitschriftentitel: | The Journal of Immunology |
---|---|
Personen und Körperschaften: | , , , , |
In: | The Journal of Immunology, 180, 2008, 8, S. 5699-5706 |
Format: | E-Article |
Sprache: | Englisch |
veröffentlicht: |
The American Association of Immunologists
|
Schlagwörter: |
Zusammenfassung: | <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> |
---|---|
Umfang: | 5699-5706 |
ISSN: |
0022-1767
1550-6606 |
DOI: | 10.4049/jimmunol.180.8.5699 |