Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

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 com...

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Detalles Bibliográficos
Autores: Salazar Roa, María, Guzmán Pastor, Manuel, Lorente Pérez, María Del Mar, Velasco Díez, Guillermo, Hernández Tiedra, Sonia, Fabriàs, Gemma, Dávila, David, Salanueva, Iñigo J., Casas, Josefina, Montes, L. Ruth, Antón, Zuriñe, GarcíaTaboada, Elena, Nylandsted, Jesper, Armstrong, Jane, López Valero, Israel, McKee, Christopher S., Serrano Puebla, Ana, García López, Roberto, González Martínez, José, Abad, José Luis, Kentaro, Hanada, Boya, Patricia, Goñi, Félix, Lovat, Penny, Jäättelä, Marja, Alonso, Alicia
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/18401
Acceso en línea:https://hdl.handle.net/20.500.14352/18401
Access Level:acceso abierto
Palabra clave:Autophagy
Cancer
Cannabinoids
Cell death
Sphingolipids
Biología molecular (Biología)
Bioquímica (Biología)
2415 Biología Molecular
2302 Bioquímica
3207 Patología
Descripción
Sumario: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.

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