title: Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression.
abstract: In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3β and nuclear translocation of β-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.
authors.affiliation: Department of Prosthodontics, Preclinical Education, and Material Science, University of Bonn, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kraus
authors.affiliation: Department of Prosthodontics, Preclinical Education, and Material Science, University of Bonn, Bonn, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Reckenbeil
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wenghoefer
authors.affiliation: Department of Prosthodontics, Preclinical Education, and Material Science, University of Bonn, Bonn, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Stark
authors.affiliation: Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Welschnonnenstr. 17, 53111, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Frentzen
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Allam
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Natalija
authors.initials: N
authors.lastname: Novak
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.affiliation: Department of Orthodontics, University of Bonn, Bonn, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Götz
authors.affiliation: Department of Nuclear Medicine, University of Bonn, Bonn, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Probstmeier
authors.affiliation: Institute of Physiology II, University of Bonn, Bonn, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Welschnonnenstr. 17, 53111, Bonn, Germany. jochen.winter@ukb.uni-bonn.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Winter
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D054439:Ghrelin / Q000032:analysis / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009055:Mouth / Q000378:metabolism / Q000473:pathology*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism
chemical_list: D054439:Ghrelin; D051272:Glucose Transporter Type 1; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D005947:Glucose
keywords: Glucose uptake; Oral squamous cell carcinoma cells; Orexigenic peptide