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Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells.
J Clin Invest 2009; 119(5):1359-72JCI

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19425170

Citation

Salazar, María, et al. "Cannabinoid Action Induces Autophagy-mediated Cell Death Through Stimulation of ER Stress in Human Glioma Cells." The Journal of Clinical Investigation, vol. 119, no. 5, 2009, pp. 1359-72.
Salazar M, Carracedo A, Salanueva IJ, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 2009;119(5):1359-72.
Salazar, M., Carracedo, A., Salanueva, I. J., Hernández-Tiedra, S., Lorente, M., Egia, A., ... Velasco, G. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. The Journal of Clinical Investigation, 119(5), pp. 1359-72.
Salazar M, et al. Cannabinoid Action Induces Autophagy-mediated Cell Death Through Stimulation of ER Stress in Human Glioma Cells. J Clin Invest. 2009;119(5):1359-72. PubMed PMID: 19425170.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. AU - Salazar,María, AU - Carracedo,Arkaitz, AU - Salanueva,Iñigo 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, PY - 2009/5/9/entrez PY - 2009/5/9/pubmed PY - 2009/6/9/medline SP - 1359 EP - 72 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 119 IS - 5 N2 - 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/19425170/abstract/ L2 - https://doi.org/10.1172/jci37948 DB - PRIME DP - Unbound Medicine ER -