title: Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1-phosphate signaling pathway in a mouse model of diethylnitrosamine-induced hepatocellular carcinoma.
abstract: The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma, but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p. beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Melatonin alleviated the distortion of normal hepatic architecture, lowered the incidence of preneoplastic/neoplastic lesions, and inhibited the expression of proliferative/cell cycle regulatory proteins (Ki67, PCNA, cyclin D1, cyclin E, CDK4, and CDK6). S1P levels and expression of SphK1, SphK2, and S1P receptors (S1PR1/S1PR3) were significantly elevated in DEN-treated mice. However, there was a decreased expression of S1P lyase. These effects were significantly abrogated in a time- and dose-dependent manner by melatonin, which also increased S1PR2 expression. Following DEN treatment, mice exhibited increased phosphorylation of PI3K, AKT, mTOR, STAT3, ERK, and p38, and a higher expression of NF-κB p50 and p65 subunits. Melatonin administration significantly inhibited those changes. Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the protective effects of melatonin in hepatocarcinogenesis.
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors.forename: Diana I
authors.initials: DI
authors.lastname: Sánchez
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: González-Fernández
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: San-Miguel
authors.affiliation: Pharmacy Service, Complejo Asistencial Universitario de León, León, Spain.
authors.forename: Juan Ortiz
authors.initials: JO
authors.lastname: de Urbina
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Crespo
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Tuñón
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D002273:Carcinogens; D004052:Diethylnitrosamine; D008246:Lysophospholipids; D008550:Melatonin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: diethylnitrosamine; hepatocellular carcinoma; melatonin; sphingosine 1-phosphate; sphingosine kinase 1