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Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
María Salazar, … , Patricia Boya, Guillermo Velasco
María Salazar, … , Patricia Boya, Guillermo Velasco
Published April 1, 2009
Citation Information: J Clin Invest. 2009;119(5):1359-1372. https://doi.org/10.1172/JCI37948.
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Research Article Oncology

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

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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 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.

Authors

María Salazar, Arkaitz Carracedo, Íñigo J. Salanueva, Sonia Hernández-Tiedra, Mar Lorente, Ainara Egia, Patricia Vázquez, Cristina Blázquez, Sofía Torres, Stephane García, Jonathan Nowak, Gian María Fimia, Mauro Piacentini, Francesco Cecconi, Pier Paolo Pandolfi, Luis González-Feria, Juan L. Iovanna, Manuel Guzmán, Patricia Boya, Guillermo Velasco

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Figure 2

ER stress precedes autophagy in cannabinoid action.

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ER stress precedes autophagy in cannabinoid action.
(A) Effect of THC on...
(A) Effect of THC on U87MG cell morphology. Note the presence of the dilated ER in THC- but not vehicle-treated cells (6 h). Arrows point to the ER. Scale bars: 500 nm. (B) Effect of SR1 (1 μM) and THC on PDI immunostaining (red) in U87MG cells (8 h; n = 3). The percentage of cells with PDI dots relative to the total cell number is shown in the corner of each panel (mean ± SD). Scale bar: 20 μm. (C) Effect of SR1 (1 μM) on THC-induced eIF2α phosphorylation of U87MG cells (3 h; OD relative to vehicle-treated cells, mean ± SD; n = 3). (D) Effect of THC on PDI (red) and LC3 (green) immunostaining in U87MG cells (n = 3). The percentage of cells with PDI or LC3 dots relative to total cell number at each time point (mean ± SD) is shown. Scale bar: 20 μm. (E) Effect of THC on eIF2α phosphorylation and LC3 lipidation in U87MG cells (n = 3). **P < 0.01 compared with THC-treated (B) or vehicle-treated (C and D) cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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