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, I., Hernández Tiedra, S., Lorente, M., Egia, A., et al. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. THE JOURNAL OF CLINICAL INVESTIGATION, 119(5), 1359-1372 [10.1172/JCI37948.].

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

PIACENTINI, MAURO;CECCONI, FRANCESCO;
2009-05-01

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.
mag-2009
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/06 - ANATOMIA COMPARATA E CITOLOGIA
English
Con Impact Factor ISI
Eukaryotic Initiation Factor-2; Endoplasmic Reticulum; Autophagy; Neoplasm Proteins; Repressor Proteins; Cell Death; Cell Line, Transformed; Cell Line, Tumor; Enzyme Inhibitors; Tetrahydrocannabinol; Microtubule-Associated Proteins; Mice; Transcription Factors; Cell Cycle Proteins; Models, Biological; Phosphorylation; Protein-Serine-Threonine Kinases; Cannabinoids; Basic Helix-Loop-Helix Transcription Factors; Amino Acid Chloromethyl Ketones; Animals; Glioma; Humans; Apoptosis; Xenograft Model Antitumor Assays; Caspase 3; Ribosomal Protein S6 Kinases; Proto-Oncogene Proteins c-akt
Salazar, M., Carracedo, A., Salanueva, I., Hernández Tiedra, S., Lorente, M., Egia, A., et al. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. THE JOURNAL OF CLINICAL INVESTIGATION, 119(5), 1359-1372 [10.1172/JCI37948.].
Salazar, M; Carracedo, A; Salanueva, I; Hernández Tiedra, S; Lorente, M; Egia, A; Vázquez, P; Blázquez, C; Torres, S; García, S; Nowak, J; Fimia, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/19323
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