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Autophagy. 2016 Nov;12(11):2213-2229. Epub 2016 Sep 16.

Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.

Author information

1
a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.
2
b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
3
c Research Unit on BioActive Molecules (RUBAM) , Departments of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , Spain.
4
d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain.
5
e Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center (DCRC) , Copenhagen , Denmark.
6
f Dermatological Sciences , Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne , UK.
7
g Faculty of Applied Sciences, University of Sunderland , Sunderland , UK.
8
h Departament of Cellular and Molecular Biology , Centro de Investigaciones Biológicas, CSIC , Madrid , Spain.
9
i Department of Biochemistry and Cell Biology , National Institute of Infectious Diseases , Shinjuku-ku, Tokyo , Japan.
10
j Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain, Instituto Universitario de Investigación Neuroquímica, Complutense University , Madrid , Spain.

Abstract

Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ9-tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.

KEYWORDS:

autophagy; cancer; cannabinoids; cell death; sphingolipids

PMID:
27635674
PMCID:
PMC5103338
DOI:
10.1080/15548627.2016.1213927
[Indexed for MEDLINE]
Free PMC Article

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