title: The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action.
abstract: Δ(9)-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 RasV(12)/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.
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Salazar
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.forename: Elena
authors.initials: E
authors.lastname: García-Taboada
authors.forename: Sonia
authors.initials: S
authors.lastname: Hernández-Tiedra
authors.forename: David
authors.initials: D
authors.lastname: Davila
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Endre
authors.initials: E
authors.lastname: Kiss-Toth
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
mesh_terms: D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology*; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D046912:Multiprotein Complexes; C474830:TRB3 protein, mouse; D013759:Dronabinol; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: ATF-4; Apoptosis; Autophagy; C/EBP homologous protein; CB(1); CB(2); CHOP; Cancer; Cannabinoids; Cell signaling; ER; MEF; THC; TRIB3; Tumor xenografts; activating transcription factor 4; cannabinoid type-1 receptor; cannabinoid type-2 receptor; endoplasmic reticulum; mTORC1; mTORC2; mammalian target of rapamycin complex 1; mammalian target of rapamycin complex 2; mouse embryonic fibroblast; tribbles-homologue 3; Δ(9)-tetrahydrocannabinol