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Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

AuthorsSalazar, María; Carracedo, Arkaitz; Salanueva, Íñigo J.; Hernández-Tiedra, Sonia; Lorente, Mar; Egia, Ainara; Vázquez Pérez, Patricia ; Blázquez, Cristina; Torres, Sofía ; García, Stéphane; Nowak, Jonathan; Fimia, Gian María; Piacentini, Mauro; Cecconi, Francesco; Pandolfi, Pier Paolo; González-Feria, Luis; Iovanna, Juan Lucio; Guzmán, Manuel; Boya, Patricia ; Velasco, Guillermo
KeywordsCancer cells
Human glioma cell death
Antitumor action
Δ9-Tetrahydrocannabinol (THC)
Issue Date1-Apr-2009
PublisherAmerican Society for Clinical Investigation
CitationThe Journal of Clinical Investigation 119(5):1359–1372(2009)
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.
Description14 pages, 8 figures.
Publisher version (URL)http://dx.doi.org/10.1172/JCI37948
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