Portal de Periódicos da CAPES

Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

2016; Taylor & Francis; Volume: 12; Issue: 11 Linguagem: Inglês

10.1080/15548627.2016.1213927

1554-8635

Sonia Hernández‐Tiedra, Gemma Fabriàs, David Dávila, Íñigo J. Salanueva, Josefina Casas, L. Ruth Montes, Zuriñe Antón, Elena García-Taboada, María Salazar‐Roa, Mar Lorente, Jesper Nylandsted, Jane L. Armstrong, Israel López-Valero, Christopher S. McKee, Ana Serrano‐Puebla, Roberto García-López, José González‐Martínez, José Luı́s Abad, Kentaro Hanada, Patricia Boya, Félix M. Goñi, Manuel Guzmán, Penny E. Lovat, Marja Jäättelä, Alicia Alonso, Guillermo Velasco,

Sleep and Wakefulness Research

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.