title: Rap1 mediates galanin receptor 2-induced proliferation and survival in squamous cell carcinoma.
abstract: Previously we showed that galanin, a neuropeptide, is secreted by human squamous cell carcinoma of the head and neck (SCCHN) in which it exhibits an autocrine mitogenic effect. We also showed that rap1, a ras-like signaling protein, is a critical mediator of SCCHN progression. Given the emerging importance of the galanin cascade in regulating proliferation and survival, we investigated the effect of GAL on SCCHN progression via induction of galanin receptor 2 (GALR2)-mediated rap1 activation. Studies were performed in multiple SCCHN cell lines by inducing endogenous GALR2, by stably overexpressing GALR2 and by downregulating endogenous GALR2 with siGALR2. Cell proliferation and survival, mediated by the ERK and AKT signaling cascades, respectively, were evaluated by functional and immunoblot analysis. The role of rap1 in GALR2-mediated proliferation and survival was evaluated by modulating expression. Finally, the effect of GALR2 on tumor growth was determined. GALR2 stimulated proliferation and survival via ERK and AKT activation, respectively. Knockdown or inactivation of rap1 inhibited GALR2-induced, AKT and ERK-mediated survival and proliferation. Overexpression of GALR2 promoted tumor growth in vivo. GALR2 promotes proliferation and survival in vitro, and promotes tumor growth in vivo, consistent with an oncogenic role for GALR2 in SCCHN.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, The University of Michigan, 1011 N. University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Banerjee
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Henson
authors.forename: Nickole
authors.initials: N
authors.lastname: Russo
authors.forename: Alex
authors.initials: A
authors.lastname: Tsodikov
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006160:Guanosine Triphosphate / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D047368:Tumor Burden
chemical_list: D020690:GTPase-Activating Proteins; C484658:RAP1GAP protein, human; D012333:RNA, Messenger; D044092:Receptor, Galanin, Type 2; D006160:Guanosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases