In:
Journal of Pineal Research, Wiley, Vol. 59, No. 2 ( 2015-09), p. 178-189
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 m m ) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin‐1 expression, p62 degradation, and LC 3 II and LAMP ‐2 colocalization, which translated in decreased cell viability. Moreover, ATG 5 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 ( ASM ase) stimulation. Serine palmitoyltransferase ( SPT ) inhibition with myriocin prevented melatonin‐induced autophagy and ASM ase inhibition with imipramine‐impaired autophagy flux. However, ASM ase 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 ASM ase‐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.
Type of Medium:
Online Resource
ISSN:
0742-3098
,
1600-079X
DOI:
10.1111/jpi.2015.59.issue-2
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2027992-9
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