RT info:eu-repo/semantics/preprint
T1 Ceramide metabolism regulates autophagy and apoptotic-cell death induced by melatonin in liver cancer cells
A1 Ordoñez, Raquel
A1 Fernández, Ana
A1 Prieto-Domínguez, Néstor
A1 Martínez, Laura
A1 García-Ruiz, Carmen
A1 Fernández-Checa, José C.
A1 Mauriz Gutiérrez, José Luis
A1 González Gallego, Javier
A2 Otros
K1 Medicina. Salud
K1 Melatonin
K1 Hepatocarcinoma
K1 Autophagy
K1 Ceramides
K1 Palmitoyltransferase
K1 Apoptosis
AB Autophagy is a process that maintains homeostasis during stress, although it alsocontributes to cell death under specific contexts. Ceramides have emerged as importanteffectors in the regulation of autophagy, mediating the crosstalk with apoptosis. Melatonininduces apoptosis of cancer cells; however, its role in autophagy and ceramide metabolismhas yet to be clearly elucidated. This study was aimed to evaluate the effect of melatoninadministration on autophagy and ceramide metabolism and its possible link with melatonininducedapoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mM) transientlyinduced autophagy in HepG2 cells through JNK phosphorylation, characterized by increasedBeclin1 expression, p62 degradation and LC3II and LAMP2 colocalization, which translatedin decreased cell viability. Moreover, ATG5-silencing sensitized HepG2 cells to melatonininduced-apoptosis, suggesting a dual role of autophagy in cell death. Melatonin enhancedceramide levels through both de novo synthesis and acid sphingomyelinase (ASMase)stimulation. Serine palmitoyl transferase (SPT) inhibition with myriocin prevented melatonininduced autophagy and ASMase inhibition with imipramine impaired autophagy flux.However, ASMase inhibition partially protected HepG2 cells against melatonin while SPTinhibition significantly enhanced cell death. Findings suggest a cross-talk between SPTmediatedceramide generation and autophagy in protecting against melatonin, while specificASMase-induced ceramide production participates in melatonin-mediated cell death. Thus,dual blocking of SPT and autophagy emerge as a potential strategy to potentiate the apoptoticeffects of melatonin in liver cancer cells
PB Wiley
YR 2016
FD 2016-12-19
LK http://hdl.handle.net/10612/5688
UL http://hdl.handle.net/10612/5688
NO Journal of Pineal Research, 2015, 59
NO P. 178-189
DS BULERIA. Repositorio Institucional de la Universidad de León
RD 27-abr-2024