Cancer Biology and Signal Transduction The G Protein–Coupled Receptor GALR2 Promotes Angiogenesis in Head and Neck Cancer

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive diseasewith poor patient survival. Galanin receptor 2 (GALR2) is a G protein–coupled receptor that induces aggressive tumor growth in SCCHN. The objective of this studywas to investigate themechanismbywhichGALR2promotes 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 relevantmouse orthotopic floor-of-mouthmodels. 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.