Ceramide metabolism regulates autophagy and apoptotic-cell death induced by melatonin in liver cancer cells

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Ceramide metabolism regulates autophagy and apoptotic-cell death induced by melatonin in liver cancer cells

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Title: Ceramide metabolism regulates autophagy and apoptotic-cell death induced by melatonin in liver cancer cells
Author: Ordoñez, Raquel;Fernández, Ana;Prieto-Domínguez, Néstor;Martínez, Laura;García-Ruiz, Carmen;Fernández-Checa, José C.;Mauriz, José L.;González-Gallego, Javier
xmlui.dri2xhtml.METS-1.0.item-contributor: Instituto Universitario de Biomedicina (IBIOMED)
xmlui.dri2xhtml.METS-1.0.item-area: Otros
Abstract: 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 melatonininduced apoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mM) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin1 expression, p62 degradation and LC3II and LAMP2 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 palmitoyl transferase (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 cross-talk between SPTmediated 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 emerge as a potential strategy to potentiate the apoptotic effects of melatonin in liver cancer cells
xmlui.dri2xhtml.METS-1.0.item-desfisica: P. 178-189
Publisher: Wiley
xmlui.dri2xhtml.METS-1.0.item-citation: Journal of Pineal Research, 2015, 59
URI: http://hdl.handle.net/10612/5688
Date: 2015-04-23
xmlui.dri2xhtml.METS-1.0.item-tipo: info:eu-repo/semantics/preprint
Subject: Medicina. Salud
xmlui.dri2xhtml.METS-1.0.item-palclave: Melatonin
Hepatocarcinoma
Autophagy
Ceramides
Palmitoyltransferase
Apoptosis
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