Salazar Roa, MaríaCarracedo, ArkaitzSalanueva, IñigoHernandez-Tiedra, SoniaLorente, MarEgia, AinaraVazquez, PatriciaBlazquez, CristinaTorres, SofiaGarcia, StephaneNowak, JonathanFimia, Gian MaríaPiacentini, MauroCecconi, FrancescoPandolfi, Pier PaolaGonzalez-Feria, LuisIovanna, JuanGuzman, ManuelBoya, PatriciaVelasco, Guillermo2024-01-242024-01-242009Salazar, María, et al. «Cannabinoid Action Induces Autophagy-Mediated Cell Death through Stimulation of ER Stress in Human Glioma Cells». Journal of Clinical Investigation, vol. 119, n.o 5, mayo de 2009, pp. 1359-72. https://doi.org/10.1172/JCI37948.0021-973810.1172/JCI37948https://hdl.handle.net/20.500.14352/95038This work was supported by grants from the Spanish Ministry of Education and Science (MEC) (HF2005/0021, to G. Velasco; SAF2006/00918, to M. Guzmán; and BFU2006-00508, to P. Boya), Santander-Complutense PR34/07-15856, to G. Velasco), Comunidad de Madrid (S-SAL/0261/2006, to M. Guzmán), and La Ligue contre le Cancer and Canceropole PACA (to J.L. Iovanna). M. Salazar was the recipient of a fellowship from the MEC. A. Carracedo was the recipient of fellowships from Gobierno Vasco, the Federation of European Biochemical Societies, and the European Molecular Biology Organization. M. Lorente and P. Boya have a Juan de la Cierva and a Ramón y Cajal contract from the MEC, respectively. S. Hernández-Tiedra has a technician contract from the Spanish Ministry of Education and the Fondo Social Europeo.Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3–dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.engjournal article1558-8238https://doi.org/10.1172/JCI37948open access576.353616. 831-006. 484577.175.82CancerGliomasAKt-mTOR axisTribblesAutophagyCannabinoidsBiología molecular (Biología)Bioquímica (Biología)Oncología2403 Bioquímica2407 Biología Celular2415 Biología Molecular3201.01 Oncología