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
J. Clin. Invest. 2009; 119(5):1359
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.
- Autophagy mediates THC-induced cancer cell death.
- THC induces autophagy via ER stress–dependent upregulation of p8 and TRB3.
- THC inhibits Akt and mTORC1 via TRB3.
- THC-induced autophagy promotes the apoptotic death of cancer cells.
- Activation of autophagy is necessary for cannabinoid antitumoral action in vivo.
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
J. Clin. Invest. 119:5 doi:10.1172/JCI37948 [Go to this article.]
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Published in Volume 119, Issue 5 (May 1,2009)
J. Clin. Invest. 119(5): 1359-1372 (2009). doi:10.1172/JCI37948.