title: G protein-coupled receptor kinase 6 deficiency promotes angiogenesis, tumor progression, and metastasis.
abstract: G protein-coupled receptor kinases (GRKs) phosphorylate the activated form of G protein-coupled receptors leading to receptor desensitization and downregulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis, and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6(-/-)) exhibited a significant increase in Lewis lung cancer growth and metastasis relative to control littermates (GRK6(+/+)). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor, but upregulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs, and microvessel density. Because β-arrestin-2-deficient (βarr2(-/-)) mice exhibited increased Lewis lung cancer growth and metastasis similar to that of GRK6(-/-), we developed a double GRK6(-/-)/βarr2(-/-) mouse model. Surprisingly, GRK6(-/-)/βarr2(-/-) mice exhibited faster tumor growth relative to GRK6(-/-) or βarr2(-/-) mice. Treatment of the mice with anti-CXCR2 Ab inhibited tumor growth in both GRK6(-/-) and GRK6(-/-)/βarr2(-/-) animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression, and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment, thereby promoting angiogenesis and metastasis. Because GRK6(-/-)/βarr2(-/-) showed greater tumor growth relative to GRK6(-/-) or βarr2(-/-) mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis.
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Raghuwanshi
authors.forename: Nikia
authors.initials: N
authors.lastname: Smith
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Rivers
authors.forename: Ariel J
authors.initials: AJ
authors.lastname: Thomas
authors.forename: Natalie
authors.initials: N
authors.lastname: Sutton
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Xiaoxin L
authors.initials: XL
authors.lastname: Chen
authors.forename: TinChung
authors.initials: T
authors.lastname: Leung
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Richardson
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002633:Chemotaxis; D018450:Disease Progression; D015536:Down-Regulation; D054768:G-Protein-Coupled Receptor Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D008175:Lung Neoplasms / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015854:Up-Regulation; D014945:Wound Healing; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; C112019:SB 225002; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse