Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8302513 | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | 2013 | 6 Pages |
Abstract
Î9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer. This effect relies, at least in part, on the up-regulation of several endoplasmic reticulum stress-related proteins including the pseudokinase tribbles homologue-3 (TRIB3), which leads in turn to the inhibition of the AKT/mTORC1 axis and the subsequent stimulation of autophagy-mediated apoptosis in tumor cells. Here, we took advantage of the use of cells derived from Trib3-deficient mice to investigate the precise mechanisms by which TRIB3 regulates the anti-cancer action of THC. Our data show that RasV12/E1A-transformed embryonic fibroblasts derived from Trib3-deficient mice are resistant to THC-induced cell death. We also show that genetic inactivation of this protein abolishes the ability of THC to inhibit the phosphorylation of AKT and several of its downstream targets, including those involved in the regulation of the AKT/mammalian target of rapamycin complex 1 (mTORC1) axis. Our data support the idea that THC-induced TRIB3 up-regulation inhibits AKT phosphorylation by regulating the accessibility of AKT to its upstream activatory kinase (the mammalian target of rapamycin complex 2; mTORC2). Finally, we found that tumors generated by inoculation of Trib3-deficient cells in nude mice are resistant to THC anticancer action. Altogether, the observations presented here strongly support that TRIB3 plays a crucial role on THC anti-neoplastic activity. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.
Keywords
mTORC2ATF-4THCTRIB3MEFmTORC1Tumor xenograftsCB1CB2C/EBP homologous proteinΔ9-TetrahydrocannabinolAutophagyCHOPApoptosisCancerCell signalingendoplasmic reticulumactivating transcription factor 4mouse embryonic fibroblastMammalian target of rapamycin complex 2Mammalian target of rapamycin complex 1Cannabinoidscannabinoid type-1 receptorCannabinoid type-2 receptor
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Authors
MarÃa Salazar, Mar Lorente, Elena GarcÃa-Taboada, Sonia Hernández-Tiedra, David Davila, Sheila E. Francis, Manuel Guzmán, Endre Kiss-Toth, Guillermo Velasco,