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Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):264-275. doi: 10.1016/j.bbagen.2016.11.033. Epub 2016 Nov 25.

Dihydroceramide desaturase inhibitors induce autophagy via dihydroceramide-dependent and independent mechanisms.

Author information

1
Consejo Superior de Investigaciones Científicas (CSIC), Institut de Química Avançada de Catalunya (IQAC-CSIC), Departament de Química Biomèdica, Research Unit on Bioactive Molecules (RUBAM), Jordi Girona 18-26, 08034 Barcelona, Spain.
2
Consejo Superior de Investigaciones Científicas (CSIC), Institut de Química Avançada de Catalunya (IQAC-CSIC), Departament de Química Biomèdica, Research Unit on Bioactive Molecules (RUBAM), Jordi Girona 18-26, 08034 Barcelona, Spain.. Electronic address: gemma.fabrias@iqac.csic.es.

Abstract

BACKGROUND:

Autophagy consists on the delivery of cytoplasmic material and organelles to lysosomes for degradation. Research on autophagy is a growing field because deciphering the basic mechanisms of autophagy is key to understanding its role in health and disease, and to paving the way to discovering novel therapeutic strategies. Studies with chemotherapeutic drugs and pharmacological tools support a role for dihydroceramides as mediators of autophagy. However, their effect on the autophagy outcome (cell survival or death) is more controversial.

METHODS:

We have examined the capacity of structurally varied Des1 inhibitors to stimulate autophagy (LC3-II analysis), to increase dihydroceramides (mass spectrometry) and to reduce cell viability (SRB) in T98G and U87MG glioblastoma cells under different experimental conditions.

RESULTS:

The compounds activity on autophagy induction took place concomitantly with accumulation of dihydroceramides, which occurred by both stimulation of ceramide synthesis de novo and reduction of Des1 activity. However, autophagy was also induced by the test compounds after preincubation with myriocin and in cells with a reduced capacity to produce dihydroceramides (U87DND). Autophagy inhibition with 3-methyladenine in the de novo dihydroceramide synthesis competent U87MG cells increased cytotoxicity, while genetic inhibition of autophagy in U87DND cells, poorly efficient at synthesizing dihydroceramides, augmented resistance to the test compounds.

CONCLUSION:

Dihydroceramide desaturase 1 inhibitors activate autophagy via both dihydroceramide-dependent and independent pathways and the balance between the two pathways influences the final cell fate.

GENERAL SIGNIFICANCE:

The cells capacity to biosynthesize dihydroceramides must be taken into account in proautophagic Des1 inhibitors-including therapies.

KEYWORDS:

Autophagy; Cancer; Dihydroceramide desaturase; Inhibitor; Lipidomics; Sphingolipids

PMID:
27894925
DOI:
10.1016/j.bbagen.2016.11.033
[Indexed for MEDLINE]

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