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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7464748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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