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.