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

Abstract

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.

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  • Authors

    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

    Source

    The Journal of clinical investigation 119:5 2009 May pg 1359-72

    MeSH

    Amino Acid Chloromethyl Ketones
    Animals
    Apoptosis
    Autophagy
    Basic Helix-Loop-Helix Transcription Factors
    Cannabinoids
    Caspase 3
    Cell Cycle Proteins
    Cell Death
    Cell Line, Transformed
    Cell Line, Tumor
    Dronabinol
    Endoplasmic Reticulum
    Enzyme Inhibitors
    Eukaryotic Initiation Factor-2
    Glioma
    Humans
    Mice
    Microtubule-Associated Proteins
    Models, Biological
    Multiprotein Complexes
    Neoplasm Proteins
    Phosphorylation
    Protein-Serine-Threonine Kinases
    Proteins
    Proto-Oncogene Proteins c-akt
    Repressor Proteins
    Ribosomal Protein S6 Kinases
    TOR Serine-Threonine Kinases
    Transcription Factors
    Xenograft Model Antitumor Assays

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19425170