Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

Hernandez-Tiedra, Sonia, Fabrias, Gemma, Davila, David, Salanueva, Inigo J, Casas, Josefina, Montes, L Ruth, Anton, Zurine, Garcia-Taboada, Elena, Salazar-Roa, Maria, Lorente, Mar, Nylandsted, Jesper, Armstrong, Jane, Lopez-Valero, Israel, McKee, Christopher, Serrano-Puebla, Ana, Garcia-Lopez, Roberto, Gonzalez-Martinez, Jose, Abad, Jose L, Hanada, Kentaro, Boya, Patricia, Goni, Felix M, Guzman, Manuel, Lovat, Penny, Jaattela, Marja, Alonso, Alicia and Velasco, Guillermo (2016) Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy, 12 (11). pp. 2213-2229. ISSN 1554-8627

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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.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences
Depositing User: Jane Armstrong
Date Deposited: 23 Sep 2016 14:23
Last Modified: 04 Feb 2020 11:27
URI: http://sure.sunderland.ac.uk/id/eprint/6544
ORCID for Jane Armstrong: ORCID iD orcid.org/0000-0002-5822-0597

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