Galanin receptor 1 has anti-proliferative effects in oral squamous cell carcinoma.
In the United States, oral cancer accounts for more deaths annually than cervical cancer, leukemias, or Hodgkin's lymphoma. Studies have shown that aberrations of chromosome 18q develop with tumor progression and are associated with significantly decreased survival in head and neck cancer patients. The G-protein-coupled receptor, galanin receptor 1 (GALR1), maps to this region of chromosome 18q. Although the role of GALR1 has been well characterized in neuronal cells, little is known regarding this receptor in non-neuronal cells. In this study, the expression, mitogenic function, and signaling mechanism of GALR1 are investigated in normal and malignant oral epithelial cells. mRNA expression was determined via reverse transcriptase-PCR. Protein quantification was done via immunoblot analysis and enzyme-linked immunosorbent assay. For functional and signaling studies, an inhibitory antibody was generated to the N-terminal ligand binding domain of GALR1. GALR1 protein and mRNA expression and GAL secretion were detected at variable levels in immortalized human oral keratinocytes and human oropharyngeal squamous cell carcinoma cell lines. Upon competitive inhibition of GALR1, proliferation was up-regulated in immortalized and malignant keratinocytes. Furthermore, studies with the inhibitory antibody and U0126, the MAPK inhibitor, show that GALR1 inhibits proliferation in immortalized and malignant keratinocytes by inactivating the MAPK pathway. GALR1s inhibitory effects on proliferation in epithelial cells raises the possibility that inactivation or disregulation of this receptor can lead to uncontrolled proliferation and neoplastic transformation.
Henson
Bradley S
BS
Department of Oral Medicine, Pathology, and Oncology, University of Michigan School of Dentistry, Ann Arbor, 48109-0506, USA.
Neubig
Richard R
RR
Jang
Ilwhan
I
Ogawa
Tetsuya
T
Zhang
Zhaocheng
Z
Carey
Thomas E
TE
D'Silva
Nisha J
NJ
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002070:Butadienes / Q000494:pharmacology; D016466:CHO Cells; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002887:Chromosomes, Human, Pair 18; D006224:Cricetinae; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D019004:Galanin / Q000737:chemistry*; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009062:Mouth Neoplasms / Q000188:drug therapy*; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D044091:Receptor, Galanin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism; D044093:Receptor, Galanin, Type 3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D000906:Antibodies; D000970:Antineoplastic Agents; D002070:Butadienes; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D008024:Ligands; D009570:Nitriles; D012333:RNA, Messenger; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D044093:Receptor, Galanin, Type 3; C113580:U 0126; D019004:Galanin