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The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action.
Biochim Biophys Acta. 2013 Oct; 1831(10):1573-8.BB

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+Show Affiliations

Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23567453

Citation

Salazar, María, et al. "The Pseudokinase Tribbles Homologue-3 Plays a Crucial Role in Cannabinoid Anticancer Action." Biochimica Et Biophysica Acta, vol. 1831, no. 10, 2013, pp. 1573-8.
Salazar M, Lorente M, García-Taboada E, et al. The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta. 2013;1831(10):1573-8.
Salazar, M., Lorente, M., García-Taboada, E., Hernández-Tiedra, S., Davila, D., Francis, S. E., Guzmán, M., Kiss-Toth, E., & Velasco, G. (2013). The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochimica Et Biophysica Acta, 1831(10), 1573-8. https://doi.org/10.1016/j.bbalip.2013.03.014
Salazar M, et al. The Pseudokinase Tribbles Homologue-3 Plays a Crucial Role in Cannabinoid Anticancer Action. Biochim Biophys Acta. 2013;1831(10):1573-8. PubMed PMID: 23567453.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. AU - Salazar,María, AU - Lorente,Mar, AU - García-Taboada,Elena, AU - Hernández-Tiedra,Sonia, AU - Davila,David, AU - Francis,Sheila E, AU - Guzmán,Manuel, AU - Kiss-Toth,Endre, AU - Velasco,Guillermo, Y1 - 2013/04/06/ PY - 2013/02/26/received PY - 2013/03/27/accepted PY - 2013/4/10/entrez PY - 2013/4/10/pubmed PY - 2013/12/16/medline KW - ATF-4 KW - Apoptosis KW - Autophagy KW - C/EBP homologous protein KW - CB(1) KW - CB(2) KW - CHOP KW - Cancer KW - Cannabinoids KW - Cell signaling KW - ER KW - MEF KW - THC KW - TRIB3 KW - Tumor xenografts KW - activating transcription factor 4 KW - cannabinoid type-1 receptor KW - cannabinoid type-2 receptor KW - endoplasmic reticulum KW - mTORC1 KW - mTORC2 KW - mammalian target of rapamycin complex 1 KW - mammalian target of rapamycin complex 2 KW - mouse embryonic fibroblast KW - tribbles-homologue 3 KW - Δ(9)-tetrahydrocannabinol SP - 1573 EP - 8 JF - Biochimica et biophysica acta JO - Biochim Biophys Acta VL - 1831 IS - 10 N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/23567453/The_pseudokinase_tribbles_homologue_3_plays_a_crucial_role_in_cannabinoid_anticancer_action_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1388-1981(13)00085-1 DB - PRIME DP - Unbound Medicine ER -