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Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favo...

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Autores principales: Belisario, Dimas Carolina, Kopecka, Joanna, Pasino, Martina, Akman, Muhlis, De Smaele, Enrico, Donadelli, Massimo, Riganti, Chiara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761956/
https://www.ncbi.nlm.nih.gov/pubmed/33291643
http://dx.doi.org/10.3390/cells9122598
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author Belisario, Dimas Carolina
Kopecka, Joanna
Pasino, Martina
Akman, Muhlis
De Smaele, Enrico
Donadelli, Massimo
Riganti, Chiara
author_facet Belisario, Dimas Carolina
Kopecka, Joanna
Pasino, Martina
Akman, Muhlis
De Smaele, Enrico
Donadelli, Massimo
Riganti, Chiara
author_sort Belisario, Dimas Carolina
collection PubMed
description Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.
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spelling pubmed-77619562020-12-26 Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance Belisario, Dimas Carolina Kopecka, Joanna Pasino, Martina Akman, Muhlis De Smaele, Enrico Donadelli, Massimo Riganti, Chiara Cells Review Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells. MDPI 2020-12-04 /pmc/articles/PMC7761956/ /pubmed/33291643 http://dx.doi.org/10.3390/cells9122598 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 Review
Belisario, Dimas Carolina
Kopecka, Joanna
Pasino, Martina
Akman, Muhlis
De Smaele, Enrico
Donadelli, Massimo
Riganti, Chiara
Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title_full Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title_fullStr Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title_full_unstemmed Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title_short Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
title_sort hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761956/
https://www.ncbi.nlm.nih.gov/pubmed/33291643
http://dx.doi.org/10.3390/cells9122598
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