TY - JOUR AU - Salazar, María AU - Carracedo, Arkaitz AU - Salanueva, Íñigo J. AU - Hernández-Tiedra, Sonia AU - Lorente, Mar AU - Egia, Ainara AU - Vázquez, Patricia AU - Blázquez, Cristina AU - Torres, Sofía AU - García, Stephane AU - Nowak, Jonathan AU - Fimia, Gian María AU - Piacentini, Mauro AU - Cecconi, Francesco AU - Pandolfi, Pier Paolo AU - González-Feria, Luis AU - Iovanna, Juan L. AU - Guzmán, Manuel AU - Boya, Patricia AU - Velasco, Guillermo T1 - Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells PY - 2009/05/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI37948 VL - 119 IS - 5 UR - https://doi.org/10.1172/JCI37948 SP - 1359 EP - 1372 PB - The American Society for Clinical Investigation ER -