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RT Journal Article SR Electronic T1 The G Protein–Coupled Receptor GALR2 Promotes Angiogenesis in Head and Neck Cancer JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 1323 OP 1333 DO 10.1158/1535-7163.MCT-13-0904 VO 13 IS 5 A1 Banerjee, Rajat A1 Van Tubergen, Elizabeth A. A1 Scanlon, Christina S. A1 Vander Broek, Robert A1 Lints, Joel P. A1 Liu, Min A1 Russo, Nickole A1 Inglehart, Ronald C. A1 Wang, Yugang A1 Polverini, Peter J. A1 Kirkwood, Keith L. A1 D'Silva, Nisha J. YR 2014 UL AB Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor patient survival. Galanin receptor 2 (GALR2) is a G protein–coupled receptor that induces aggressive tumor growth in SCCHN. The objective of this study was to investigate the mechanism by which GALR2 promotes angiogenesis, a critical oncogenic phenotype required for tumor growth. The impact of GALR2 expression on secretion of proangiogenic cytokines in multiple SCCHN cell lines was investigated by ELISA and in vitro angiogenesis assays. Chemical inhibitor and genetic knockdown strategies were used to understand the key regulators. The in vivo impact of GALR2 on angiogenesis was investigated in mouse xenograft, chick chorioallantoic membrane, and the clinically relevant mouse orthotopic floor-of-mouth models. GALR2 induced angiogenesis via p38-MAPK–mediated secretion of proangiogenic cytokines, VEGF, and interleukin-6 (IL-6). Moreover, GALR2 activated small-GTP-protein, RAP1B, thereby inducing p38-mediated inactivation of tristetraprolin (TTP), which functions to destabilize cytokine transcripts. This resulted in enhanced secretion of proangiogenic cytokines and angiogenesis in vitro and in vivo. In SCCHN cells overexpressing GALR2, inactivation of TTP increased secretion of IL-6 and VEGF, whereas inhibition of p38 activated TTP and decreased cytokine secretion. Here, we report that GALR2 stimulates tumor angiogenesis in SCCHN via p38-mediated inhibition of TTP with resultant enhanced cytokine secretion. Given that p38 inhibitors are in clinical use for inflammatory disorders, GALR2/p38-mediated cytokine secretion may be an excellent target for new adjuvant therapy in SCCHN. Mol Cancer Ther; 13(5); 1323–33. ©2014 AACR.This article is featured in Highlights of This Issue, p. 1019