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Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells.
Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that delta(9)-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 2alpha (eIF2alpha) 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.
Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, García S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, González-Feria L, Iovanna JL, Guzmán M, Boya P, Velasco G
MeSHAmino Acid Chloromethyl Ketones
Basic Helix-Loop-Helix Transcription Factors
Cell Cycle Proteins
Cell Line, Transformed
Cell Line, Tumor
Eukaryotic Initiation Factor-2
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Xenograft Model Antitumor Assays
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't