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dc.contributor.authorSalazar, María-
dc.contributor.authorCarracedo, Arkaitz-
dc.contributor.authorSalanueva, Íñigo J.-
dc.contributor.authorHernández-Tiedra, Sonia-
dc.contributor.authorLorente, Mar-
dc.contributor.authorEgia, Ainara-
dc.contributor.authorVázquez Pérez, Patricia-
dc.contributor.authorBlázquez, Cristina-
dc.contributor.authorTorres, Sofía-
dc.contributor.authorGarcía, Stéphane-
dc.contributor.authorNowak, Jonathan-
dc.contributor.authorFimia, Gian María-
dc.contributor.authorPiacentini, Mauro-
dc.contributor.authorCecconi, Francesco-
dc.contributor.authorPandolfi, Pier Paolo-
dc.contributor.authorGonzález-Feria, Luis-
dc.contributor.authorIovanna, Juan Lucio-
dc.contributor.authorGuzmán, Manuel-
dc.contributor.authorBoya, Patricia-
dc.contributor.authorVelasco, Guillermo-
dc.identifier.citationThe Journal of Clinical Investigation 119(5):1359–1372(2009)en_US
dc.description14 pages, 8 figures.en_US
dc.description.abstractAutophagy 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.en_US
dc.description.sponsorshipThis 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.en_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.subjectCancer cellsen_US
dc.subjectHuman glioma cell deathen_US
dc.subjectAntitumor actionen_US
dc.subjectΔ9-Tetrahydrocannabinol (THC)en_US
dc.titleCannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cellsen_US
dc.description.peerreviewedPeer revieweden_US
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