Abstract 2821: GRK6 deficiency promotes tumor aggressiveness and metastasis in a murine model of human lung cancer .

Abstract

G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) followed by the association of β-arrestin (βarr) with the phosphorylated receptor, desensitization and down-regulation. 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 sought to investigate the role of GRK6 in CXCR2-mediated tumorigenesis using a murine model of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of pro-angiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Treatment of the mice with a CXCR2 inhibitor (SB225002) or a murine anti-CXCR2 antibody blocked the effect of GRK6 deletion. Surprisingly, a GRK6−/−/βarr2−/− double knockout animal model exhibited faster tumor growth relative to GRK6−/− or βarr2−/− animals. Exposure of GRK6−/−/βarr2−/− mice to the anti-CXCR2 antibody totally inhibited tumor growth. This suggest that the effects of βarr2 and GRK6 knockdown in CXCR2-mediated tumor development are additive. 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. Since GRK6−/−/βarr2−/− mice showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data also suggest that CXCR2 couples to a different mechanism to mediate tumor progression and metastasis. Citation Format: Natalie Sutton, Nikia Smith, Ariel J. Thomas, Sandeep K. Raghuwanshi, Ricardo M. Richardson. GRK6 deficiency promotes tumor aggressiveness and metastasis in a murine model of human lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2013-2821

Overexpression of G Protein-Coupled Receptor Kinase 6 (GRK6) Is Associated with Progression and Poor Prognosis of Papillary Thyroid Carcinoma

“…Specifically, the function of GRK6 was shown to be suppressed in medulloblastoma by Src signaling, leading to enhanced tumor cell migration [ 13 ]. In addition, GRK6-knockout mice showed a higher risk of lung cancer metastasis [ 14 ], indicating the role of GRK6 in suppressing tumor progression. However, another study reported that GRK6 was highly expressed in hepatocellular carcinoma and was correlated with poor prognosis [ 15 ].…”

Aberrant GRK6 promoter methylation is associated with poor prognosis in hypopharyngeal squamous cell carcinoma

“…GRK6 is expressed in many human tissues, and participates in the pathological process of many diseases (7)(8)(9)(10). Recently, some studies reported GRK6 also has been implicated in various cancer metastasis, including lung cancer (11), medulloblastoma (12) and multiple myeloma (10). However, the specific roles and regulation of GRK6 in HSCC have not been investigated.…”