The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action
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2013
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García-Taboada, Elena
Hernández-Tiedra, Sonia
Dávila, David
Francis, Sheila E.
Kiss-Toth, Endre
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Elsevier
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Abstract
Δ9-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.
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Acknowledgements
This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (PS09/01401; PI12/02248, FR2009-0052 and IT2009-0053) to GV; Comunidad de Madrid (S2011/BMD-2308 to MG), GW Pharmaceuticals (to GV and MG) and Fundación Mutua Madrileña (AP101042012 to GV). Purchase of the Trib3-deficient mice (LEXKO-1947) line was funded by the Wellcome Trust. MS was recipient of a fellowship from the Spanish Ministry of Education and Science (MEC) and of a research formation contract from Comunidad de Madrid; ML was sequentially the recipient of a ‘Juan de la Cierva’ contract, a postdoctoral contract from the Spanish Ministry of Education and Science (MEC) and a postdoctoral contract from Comunidad de Madrid. We would like to thank Dr Dario Alessi (Dundee University, UK) for expert scientific and technical support and for kindly providing antibodies for the immunoprecipitation experiments. We also would like to thank other members of our laboratories for their continuous support.