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Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition

Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isof...

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Autores principales: Arasanz, Hugo, Hernández, Carlos, Bocanegra, Ana, Chocarro, Luisa, Zuazo, Miren, Gato, Maria, Ausin, Karina, Santamaría, Enrique, Fernández-Irigoyen, Joaquín, Fernandez, Gonzalo, Santamaria, Eva, Rodríguez, Carlos, Blanco-Luquin, Idoia, Vera, Ruth, Escors, David, Kochan, Grazyna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464748/
https://www.ncbi.nlm.nih.gov/pubmed/32764385
http://dx.doi.org/10.3390/cancers12082181
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author Arasanz, Hugo
Hernández, Carlos
Bocanegra, Ana
Chocarro, Luisa
Zuazo, Miren
Gato, Maria
Ausin, Karina
Santamaría, Enrique
Fernández-Irigoyen, Joaquín
Fernandez, Gonzalo
Santamaria, Eva
Rodríguez, Carlos
Blanco-Luquin, Idoia
Vera, Ruth
Escors, David
Kochan, Grazyna
author_facet Arasanz, Hugo
Hernández, Carlos
Bocanegra, Ana
Chocarro, Luisa
Zuazo, Miren
Gato, Maria
Ausin, Karina
Santamaría, Enrique
Fernández-Irigoyen, Joaquín
Fernandez, Gonzalo
Santamaria, Eva
Rodríguez, Carlos
Blanco-Luquin, Idoia
Vera, Ruth
Escors, David
Kochan, Grazyna
author_sort Arasanz, Hugo
collection PubMed
description Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.
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spelling pubmed-74647482020-09-04 Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition Arasanz, Hugo Hernández, Carlos Bocanegra, Ana Chocarro, Luisa Zuazo, Miren Gato, Maria Ausin, Karina Santamaría, Enrique Fernández-Irigoyen, Joaquín Fernandez, Gonzalo Santamaria, Eva Rodríguez, Carlos Blanco-Luquin, Idoia Vera, Ruth Escors, David Kochan, Grazyna Cancers (Basel) Article Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models. MDPI 2020-08-05 /pmc/articles/PMC7464748/ /pubmed/32764385 http://dx.doi.org/10.3390/cancers12082181 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Arasanz, Hugo
Hernández, Carlos
Bocanegra, Ana
Chocarro, Luisa
Zuazo, Miren
Gato, Maria
Ausin, Karina
Santamaría, Enrique
Fernández-Irigoyen, Joaquín
Fernandez, Gonzalo
Santamaria, Eva
Rodríguez, Carlos
Blanco-Luquin, Idoia
Vera, Ruth
Escors, David
Kochan, Grazyna
Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title_full Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title_fullStr Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title_full_unstemmed Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title_short Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
title_sort profound reprogramming towards stemness in pancreatic cancer cells as adaptation to akt inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464748/
https://www.ncbi.nlm.nih.gov/pubmed/32764385
http://dx.doi.org/10.3390/cancers12082181
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