title: Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.
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.
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Hernández-Tiedra
authors.affiliation: c Research Unit on BioActive Molecules (RUBAM) , Departments of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: David
authors.initials: D
authors.lastname: Dávila
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.
authors.forename: Íñigo J
authors.initials: ÍJ
authors.lastname: Salanueva
authors.affiliation: c Research Unit on BioActive Molecules (RUBAM) , Departments of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain.
authors.forename: L Ruth
authors.initials: LR
authors.lastname: Montes
authors.affiliation: d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain.
authors.forename: Zuriñe
authors.initials: Z
authors.lastname: Antón
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Taboada
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.
authors.forename: María
authors.initials: M
authors.lastname: Salazar-Roa
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.affiliation: e Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center (DCRC) , Copenhagen , Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Nylandsted
authors.affiliation: f Dermatological Sciences , Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne , UK.|g Faculty of Applied Sciences, University of Sunderland , Sunderland , UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: López-Valero
authors.affiliation: f Dermatological Sciences , Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne , UK.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: McKee
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|h Departament of Cellular and Molecular Biology , Centro de Investigaciones Biológicas, CSIC , Madrid , Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Serrano-Puebla
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: García-López
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: José
authors.initials: J
authors.lastname: González-Martínez
authors.affiliation: c Research Unit on BioActive Molecules (RUBAM) , Departments of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Abad
authors.affiliation: i Department of Biochemistry and Cell Biology , National Institute of Infectious Diseases , Shinjuku-ku, Tokyo , Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hanada
authors.affiliation: h Departament of Cellular and Molecular Biology , Centro de Investigaciones Biológicas, CSIC , Madrid , Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Boya
authors.affiliation: d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Goñi
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|j Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain, Instituto Universitario de Investigación Neuroquímica, Complutense University , Madrid , Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: f Dermatological Sciences , Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne , UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Lovat
authors.affiliation: e Unit of Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center (DCRC) , Copenhagen , Denmark.
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.affiliation: d Biofisika Institute (UPV/EHU, CSIC) , and Departamento de Bioquímica, Universidad del País Vasco, Barrio Sarriena s/n , Leioa , Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Alonso
authors.affiliation: a Department of Biochemistry and Molecular Biology I , School of Biology, Complutense University , Madrid , Spain.|b Instituto de Investigaciones Sanitarias San Carlos (IdISSC) , Madrid , Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D010539:Permeability; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013107:Sphingolipids / Q000096:biosynthesis
chemical_list: D002518:Ceramides; D013107:Sphingolipids; C109343:dihydroceramide; D013759:Dronabinol
keywords: autophagy; cancer; cannabinoids; cell death; sphingolipids