Ceramide metabolism regulates autophagy and apoptotic-cell death induced by melatonin in liver cancer cells
| Autor: | José C. Fernández-Checa, José L. Mauriz, Javier González-Gallego, Anna Fernández, Laura Martínez, Raquel Ordóñez, Néstor Prieto-Domínguez, Carmen García-Ruiz |
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| Přispěvatelé: | Otros, Instituto Universitario de Biomedicina (IBIOMED), Ministerio de Educación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Fundació La Marató de TV3, Fundación Mutua Madrileña, National Institutes of Health (US) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Ceramide Programmed cell death Hepatocarcinoma ATG5 Palmitoyltransferase melatonin Apoptosis Ceramides Article serine palmitoyltransferase Melatonin chemistry.chemical_compound Endocrinology Internal medicine medicine Autophagy Humans acid sphingomyelinase ceramides Medicina. Salud Chemistry Liver Neoplasms Hep G2 Cells Cell biology Neoplasm Proteins Gene Expression Regulation Neoplastic hepatocarcinoma Cancer cell Acid sphingomyelinase hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Autophagy is a process that maintains homeostasis during stress, although it also contributes to cell death under specific contexts. Ceramides have emerged as important effectors in the regulation of autophagy, mediating the crosstalk with apoptosis. Melatonin induces apoptosis of cancer cells; however, its role in autophagy and ceramide metabolism has yet to be clearly elucidated. This study was aimed to evaluate the effect of melatonin administration on autophagy and ceramide metabolism and its possible link with melatonin-induced apoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mm) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin-1 expression, p62 degradation, and LC3II and LAMP-2 colocalization, which translated in decreased cell viability. Moreover, ATG5 silencing sensitized HepG2 cells to melatonin-induced apoptosis, suggesting a dual role of autophagy in cell death. Melatonin enhanced ceramide levels through both de novo synthesis and acid sphingomyelinase (ASMase) stimulation. Serine palmitoyltransferase (SPT) inhibition with myriocin prevented melatonin-induced autophagy and ASMase inhibition with imipramine-impaired autophagy flux. However, ASMase inhibition partially protected HepG2 cells against melatonin, while SPT inhibition significantly enhanced cell death. Findings suggest a crosstalk between SPT-mediated ceramide generation and autophagy in protecting against melatonin, while specific ASMase-induced ceramide production participates in melatonin-mediated cell death. Thus, dual blocking of SPT and autophagy emerges as a potential strategy to potentiate the apoptotic effects of melatonin in liver cancer cells. Raquel Ordoñez and Néstor Prieto-Domínguez are supported by the program ‘Formación del Profesorado Universitario’ (Becas FPU, references FPU12/01433 and FPU13/04173, respectively) from the Ministry of Education (Spain). CIBERehd is funded by Instituto de la Salud Carlos III, Spain. This work was supported in part by grants BFU2013-48141-R from Plan Nacional de I+D+I Spain, LE135U13 from Consejería de Educación de la Junta de Castilla y León, and SAF-2011-23031 and SAF-2012-34831 from Plan Nacional de I+D Spain; Fundació Marató de TV3, La Mutua Madrileña, and PI11/0325 (META) grant from the Instituto Salud Carlos III; and by the center grant P50-AA-11999 from Research Center for Liver and Pancreatic Diseases funded by NIAAA/NIH |
| Databáze: | OpenAIRE |
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