The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Erazo, Tatiana; Lorente, Mar; López Plana, Anna; Muñoz Guardiola, Pau; Fernandez-Nogueira, Patricia; García-Martinez, José A.; Bragado Domingo, Paloma; Fuster Orellana, Gemma; Salazar, María; Espadaler, Jordi; Hernández Losa, Javier; Bayascas, Jose R.; Cortal, Marc; Vidal, Laura; Gascón, Pere; Gómez Ferreria, Mariana; Alfón, José; Velasco, Guillermo; Domènech, Carles; Lizcano, José Miguel

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental design: We investigated the effect of ABTL0...

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Autores:	Erazo, Tatiana, Lorente, Mar, López Plana, Anna, Muñoz Guardiola, Pau, Fernandez-Nogueira, Patricia, García-Martinez, José A., Bragado Domingo, Paloma, Fuster Orellana, Gemma, Salazar, María, Espadaler, Jordi, Hernández Losa, Javier, Bayascas, Jose R., Cortal, Marc, Vidal, Laura, Gascón, Pere, Gómez Ferreria, Mariana, Alfón, José, Velasco, Guillermo, Domènech, Carles, Lizcano, José Miguel
Formato:	artículo
Estado:	Versión aceptada para publicación
Fecha de publicación:	2016
País:	España
Recursos:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:diposit.ub.edu:2445/207600
Acesso em linha:	https://hdl.handle.net/2445/207600
Access Level:	acceso abierto
Palavra-chave:	Tumors Proteïnes Medicaments antineoplàstics Cicle cel·lular Transducció de senyal cel·lular Apoptosi Cèl·lules canceroses Proteins Antineoplastic agents Cell cycle Cellular signal transduction Apoptosis Cancer cells

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repository_id_str
spelling	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 PseudokinaseErazo, TatianaLorente, MarLópez Plana, AnnaMuñoz Guardiola, PauFernandez-Nogueira, PatriciaGarcía-Martinez, José A.Bragado Domingo, PalomaFuster Orellana, GemmaSalazar, MaríaEspadaler, JordiHernández Losa, JavierBayascas, Jose R.Cortal, MarcVidal, LauraGascón, PereGómez Ferreria, MarianaAlfón, JoséVelasco, GuillermoDomènech, CarlesLizcano, José MiguelTumorsProteïnesMedicaments antineoplàsticsCicle cel·lularTransducció de senyal cel·lularApoptosiCèl·lules cancerosesTumorsProteinsAntineoplastic agentsCell cycleCellular signal transductionApoptosisCancer cellsPurpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.American Association for Cancer Research2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/207600Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1158/1078-0432.CCR-15-1808Clinical Cancer Research, 2016, vol. 22, num.10, p. 2508-2519https://doi.org/10.1158/1078-0432.CCR-15-1808(c) American Association for Cancer Research, 2016info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2076002026-05-27T06:46:51Z
dc.title.none.fl_str_mv	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
title	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
spellingShingle	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase Erazo, Tatiana Tumors Proteïnes Medicaments antineoplàstics Cicle cel·lular Transducció de senyal cel·lular Apoptosi Cèl·lules canceroses Tumors Proteins Antineoplastic agents Cell cycle Cellular signal transduction Apoptosis Cancer cells
title_short	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
title_full	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
title_fullStr	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
title_full_unstemmed	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
title_sort	The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
dc.creator.none.fl_str_mv	Erazo, Tatiana Lorente, Mar López Plana, Anna Muñoz Guardiola, Pau Fernandez-Nogueira, Patricia García-Martinez, José A. Bragado Domingo, Paloma Fuster Orellana, Gemma Salazar, María Espadaler, Jordi Hernández Losa, Javier Bayascas, Jose R. Cortal, Marc Vidal, Laura Gascón, Pere Gómez Ferreria, Mariana Alfón, José Velasco, Guillermo Domènech, Carles Lizcano, José Miguel
author	Erazo, Tatiana
author_facet	Erazo, Tatiana Lorente, Mar López Plana, Anna Muñoz Guardiola, Pau Fernandez-Nogueira, Patricia García-Martinez, José A. Bragado Domingo, Paloma Fuster Orellana, Gemma Salazar, María Espadaler, Jordi Hernández Losa, Javier Bayascas, Jose R. Cortal, Marc Vidal, Laura Gascón, Pere Gómez Ferreria, Mariana Alfón, José Velasco, Guillermo Domènech, Carles Lizcano, José Miguel
author_role	author
author2	Lorente, Mar López Plana, Anna Muñoz Guardiola, Pau Fernandez-Nogueira, Patricia García-Martinez, José A. Bragado Domingo, Paloma Fuster Orellana, Gemma Salazar, María Espadaler, Jordi Hernández Losa, Javier Bayascas, Jose R. Cortal, Marc Vidal, Laura Gascón, Pere Gómez Ferreria, Mariana Alfón, José Velasco, Guillermo Domènech, Carles Lizcano, José Miguel
author2_role	author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Tumors Proteïnes Medicaments antineoplàstics Cicle cel·lular Transducció de senyal cel·lular Apoptosi Cèl·lules canceroses Tumors Proteins Antineoplastic agents Cell cycle Cellular signal transduction Apoptosis Cancer cells
topic	Tumors Proteïnes Medicaments antineoplàstics Cicle cel·lular Transducció de senyal cel·lular Apoptosi Cèl·lules canceroses Tumors Proteins Antineoplastic agents Cell cycle Cellular signal transduction Apoptosis Cancer cells
description	Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.
publishDate	2016
dc.date.none.fl_str_mv	2016
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion
format	article
status_str	acceptedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/207600
url	https://hdl.handle.net/2445/207600
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Versió postprint del document publicat a: https://doi.org/10.1158/1078-0432.CCR-15-1808 Clinical Cancer Research, 2016, vol. 22, num.10, p. 2508-2519 https://doi.org/10.1158/1078-0432.CCR-15-1808
dc.rights.none.fl_str_mv	(c) American Association for Cancer Research, 2016 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	(c) American Association for Cancer Research, 2016
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	American Association for Cancer Research
publisher.none.fl_str_mv	American Association for Cancer Research
dc.source.none.fl_str_mv	Articles publicats en revistes (Biomedicina) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,223283

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

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