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

Identifieur interne : 001288 ( Istex/Curation ); précédent : 001287; suivant : 001289

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

Auteurs : Raquel Ordo Ez [Espagne] ; Anna Fernández [Espagne] ; Néstor Prieto-Domínguez [Espagne] ; Laura Martínez [Espagne] ; Carmen García-Ruiz [Espagne, États-Unis] ; José C. Fernández-Checa [Espagne, États-Unis] ; José L. Mauriz [Espagne] ; Javier González-Gallego [Espagne]

Source :

RBID : ISTEX:2E7E9C7ED7E1070AE0836E5AFBE9D987A830CB26

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 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.

Url:
DOI: 10.1111/jpi.12249

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ISTEX:2E7E9C7ED7E1070AE0836E5AFBE9D987A830CB26

Le document en format XML

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<name sortKey="Garcia Uiz, Carmen" sort="Garcia Uiz, Carmen" uniqKey="Garcia Uiz C" first="Carmen" last="García-Ruiz">Carmen García-Ruiz</name>
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<wicri:regionArea>Keck School of Medicine, USC, University of Southern California Research Center for Alcohol Liver and Pancreatic Diseases and Cirrhosis, CA, Los Angeles</wicri:regionArea>
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<name sortKey="Fernandez Heca, Jose C" sort="Fernandez Heca, Jose C" uniqKey="Fernandez Heca J" first="José C." last="Fernández-Checa">José C. Fernández-Checa</name>
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<name sortKey="Gonzalez Allego, Javier" sort="Gonzalez Allego, Javier" uniqKey="Gonzalez Allego J" first="Javier" last="González-Gallego">Javier González-Gallego</name>
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<mods:affiliation>Address reprint requests to Javier González‐Gallego, PhD MD, Institute of Biomedicine, University of León, 24071, León, Spain.E‐mail:</mods:affiliation>
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<affiliation wicri:level="1">
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<title level="j" type="main">Journal of Pineal Research</title>
<title level="j" type="alt">JOURNAL OF PINEAL RESEARCH</title>
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<idno type="eISSN">1600-079X</idno>
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<div type="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 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.</div>
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