title: The G protein-coupled receptor GALR2 promotes angiogenesis in head and neck cancer.
abstract: 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.
authors.affiliation: Authors' Affiliations: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Craniofacial Biology, The Medical University of South Carolina, Columbia, South Carolina.
authors.forename: Rajat
authors.initials: R
authors.lastname: Banerjee
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Van Tubergen
authors.forename: Christina S
authors.initials: CS
authors.lastname: Scanlon
authors.forename: Robert
authors.initials: R
authors.lastname: Vander Broek
authors.forename: Joel P
authors.initials: JP
authors.lastname: Lints
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Nickole
authors.initials: N
authors.lastname: Russo
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Inglehart
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Polverini
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D044092:Receptor, Galanin, Type 2 / Q000235:genetics / Q000378:metabolism*; D051816:Tristetraprolin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D044092:Receptor, Galanin, Type 2; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C116753:RAP1B protein, human; D020668:rap GTP-Binding Proteins