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Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

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Hernández Tiedra, Sonia and Fabriàs, Gemma and Dávila, David and Salanueva, Iñigo J. and Casas, Josefina and Montes, L.Ruth and Antón, Zuriñe and GarcíaTaboada, Elena and Salazar Roa, María and Lorente Pérez, Mar and Nylandsted, Jesper and Armstrong, Jane and López Valero, Israel and McKee, Christopher S. and Serrano Puebla, Ana and García López, Roberto and González Martínez, José and Abad, José L. and Kentaro, Hanada and Boya, Patricia and Goñi, Félix and Guzmán, Manuel and Lovat, Penny and Jäättelä, Marja and 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, ESSN: 1554-8635

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Official URL: https://doi.org/10.1080/15548627.2016.1213927



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 D9 -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
Uncontrolled Keywords:Autophagy; cancer; cannabinoids; cell death; sphingolipids
Subjects:Medical sciences > Biology > Molecular biology
Medical sciences > Biology > Biochemistry
ID Code:46554
Deposited On:23 Feb 2018 09:16
Last Modified:23 Feb 2018 09:16

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