title: Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis.
abstract: Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence, its metastatic potential and the low efficacy of conventional treatment. Inactivation of apoptosis is implicated in tumour progression and chemotherapy resistance, and has been linked to the presence of endoplasmic reticulum stress. Melatonin, the main product of the pineal gland, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects in HCC cells, but these effects still need to be confirmed in animal models. Male Wistar rats in treatment groups received diethylnitrosamine (DEN) 50 mg/kg intraperitoneally twice/once a week for 18 weeks. Melatonin was given in drinking water at 1 mg/kg/d, beginning 5 or 12 weeks after the start of DEN administration. Melatonin improved survival rates and successfully attenuated liver injury, as shown by histopathology, decreased levels of serum transaminases and reduced expression of placental glutathione S-transferase. Furthermore, melatonin treatment resulted in a significant increase of caspase 3, 8 and 9 activities, polyadenosine diphosphate (ADP) ribose polymerase (PARP) cleavage, and Bcl-associated X protein (Bax)/Bcl-2 ratio. Cytochrome c, p53 and Fas-L protein concentration were also significantly enhanced by melatonin. Melatonin induced an increased expression of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP) and immunoglobulin heavy chain-binding protein (BiP), while cyclooxygenase (COX)-2 expression decreased. Data obtained suggest that induction of apoptosis and ER stress contribute to the beneficial effects of melatonin in rats with DEN-induced HCC.
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Andrea Janz
authors.initials: AJ
authors.lastname: Moreira
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ordoñez
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Carlos Thadeu
authors.initials: CT
authors.lastname: Cerski
authors.affiliation: Graduate Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Canoas, Brazil.
authors.forename: Jaqueline Nascimento
authors.initials: JN
authors.lastname: Picada
authors.affiliation: Service of Oncology, Complejo Asistencial Universitario de León, León, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: García-Palomo
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Graduate Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Canoas, Brazil.
authors.forename: Norma Possa
authors.initials: NP
authors.lastname: Marroni
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Mauriz
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D020552:Comet Assay; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004052:Diethylnitrosamine; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D008113:Liver Neoplasms; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use*; D017208:Rats, Wistar
chemical_list: D014408:Biomarkers, Tumor; D004052:Diethylnitrosamine; D051546:Cyclooxygenase 2; D008550:Melatonin