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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
doi:10.1172/JCI37948
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A
utophagy 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.
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