Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

• Published in: Autophagy 2016-11, Vol.12 (11), p.2213-2229
• Main Authors: Hernández-Tiedra, Sonia, Fabriàs, Gemma, Dávila, David, Salanueva, Íñigo J., Casas, Josefina, Montes, L. Ruth, Antón, Zuriñe, García-Taboada, Elena, Salazar-Roa, María, Lorente, Mar, Nylandsted, Jesper, Armstrong, Jane, López-Valero, Israel, McKee, Christopher S., Serrano-Puebla, Ana, García-López, Roberto, González-Martínez, José, Abad, José L., Hanada, Kentaro, Boya, Patricia, Goñi, Félix, Guzmán, Manuel, Lovat, Penny, Jäättelä, Marja, Alonso, Alicia, Velasco, Guillermo
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; autophagy; Autophagy - drug effects; Biological Transport - drug effects; cancer; cannabinoids; cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Ceramides - pharmacology; Dronabinol - pharmacology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Humans; Intracellular Membranes - drug effects; Intracellular Membranes - metabolism; Intracellular Membranes - ultrastructure; Lysosomes - drug effects; Lysosomes - metabolism; Lysosomes - ultrastructure; Models, Biological; Neoplasms - pathology; Permeability; Phagosomes - drug effects; Phagosomes - metabolism; Phagosomes - ultrastructure; sphingolipids; Sphingolipids - biosynthesis; Translational Research Paper
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1213927

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 Δ 9 -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.