title: Galanin receptor 2 utilizes distinct signaling pathways to suppress cell proliferation and induce apoptosis in HNSCC.
abstract: Galanin and its receptors, GALR1 and GALR2, are tumor suppressors and represent therapeutic targets in head and neck squamous cell carcinoma (HNSCC). In the present study, it was demonstrated that the re‑expression of GALR1 in GALR1 and GALR2‑negative HNSCC cells suppresses tumor cell proliferation. This is mediated via extracellular‑regulated protein kinase‑1/2 (ERK1/2)‑dependent effects on the cyclin‑dependent kinase inhibitors (CKI) and cyclin D1. In combination with galanin, GALR2 also suppressed proliferation by increasing CKI and decreasing cyclin D1 levels. In contrast to GALR1, overexpression of GALR2 also induced caspase‑3‑dependent apoptosis. It was identified that in GALR2‑transfected cells, galanin induced activation of ERK1/2 and suppressed cell proliferation. Galanin stimulation also decreased the expression of cyclin D1 and induced apoptotic DNA ladder formation in GALR2‑transfected cells. Pretreatment with the ERK1/2‑specific inhibitor U0126 and pertussis toxin prevented the suppression of cyclin D1 expression, however did not affect DNA ladder formation. In conclusion, GALR2 expression in the presence of galanin exerts antitumor effects via cell cycle arrest and apoptotic pathways, and reactivation of these pathways may have therapeutic benefits in HNSCC.
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329‑0498, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431‑3192, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Misawa
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431‑3192, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Misawa
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329‑0498, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Maruta
authors.affiliation: Department of Otorhinolaryngology‑Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903‑0215, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329‑0498, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kawada
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329‑0498, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nagatomo
authors.affiliation: Department of Otolaryngology‑Head and Neck Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329‑0498, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ichimura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019004:Galanin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D009570:Nitriles / Q000494:pharmacology; D044092:Receptor, Galanin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D009570:Nitriles; D044092:Receptor, Galanin, Type 2; C113580:U 0126; D019938:Cyclin D1; D019004:Galanin; C505407:CASP3 protein, human; D053148:Caspase 3