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

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 8

THC administration promotes autophagy in glioblastomas of 2 patients.

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THC administration promotes autophagy in glioblastomas of 2 patients. An...
Analysis of different parameters in 2 patients with glioblastoma multiforme before and after intracranial THC treatment (it was estimated that doses of 6–10 μM were reached at the site of administration). (A) TRB3 and p-S6 immunostaining. Representative photomicrographs are shown. Numbers indicate the TRB3- or p-S6–stained area normalized to the total number of nuclei in each section (mean fold change ± SD) relative to the corresponding pre-treatment sample. Fifteen sections were counted for each tumor and each condition (before and after treatment). Scale bar: 50 μm. (B) Representative photomicrographs of LC3 diaminobenzidine immunostaining. The mean percentage of cells with LC3 dots ± SD relative to the total number of nuclei in each section is noted in the corner of each panel. Ten sections were counted from each biopsy for each condition. Arrows point to cells with LC3 dots. Scale bar: 20 μm. (C) Representative photomicrographs of active caspase-3 diaminobenzidine immunostaining. Numbers indicate the percentage of cells with active caspase-3 staining ± SD relative to the total number of nuclei in each section. Ten sections were counted from each biopsy for each condition. Arrows point to cells with active caspase-3 staining. Scale bar: 20 μm. *P < 0.05 and **P < 0.01 compared with before treatment.