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

doi:10.3390/cells9122598

Cited by 134Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismCancer Cells and Metastasis

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

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Belisario, Dimas Carolina, Kopecka, Joanna, Pasino, Martina, Akman, Muhlis, De Smaele, Enrico, Donadelli, Massimo, Riganti, Chiara·2020·Cells

DOI 10.3390/cells9122598PMC PMC7761956

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Abstract

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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In hypoxia, NRF2 activates HIF1α and an array of multidrug resistance genes (MDR1/ABCB1, MRP1/ABCC1, BCRP/ABCG2) resulting in resistance to a variety of other chemotherapeutics.
“On the other hand, in hypoxia oxygenic stress response is activated by NRF2, which activates HIF1α, but more importantly an array of multidrug resistance genes such as MDR1/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 resulting in resistance to a variety of other chemotherapeutics [59, 60].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [60]

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Metabolomics in Autoimmune Diseases: Focus on Rheumatoid Arthritis, Systemic Lupus Erythematous, and Multiple Sclerosis
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Acquired non-thermal plasma resistance mediates a shift towards aerobic glycolysis and ferroptotic cell death in melanoma
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Hypoxia modeling techniques: A review
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Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers
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Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion
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Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses
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Clinical application and drug resistance mechanism of gemcitabine
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A photothermal driven chemotherapy for the treatment of metastatic melanoma
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Authors: Belisario, D. C., Kopecka, J., Pasino, M., Akman, M., De Smaele, E., Donadelli, M., & Riganti, C.
Affiliations: University of Turin (IT)
Department of Experimental Medicine, Sapienza University of Roma, 00185 Roma, Italy
University of Verona (IT)
Corresponding author: Riganti, Chiara
ORCID: Kopecka, Joanna
Akman, Muhlis
Donadelli, Massimo
Riganti, Chiara
Venue: Cells
Publisher: MDPI AG
Published: 2020-12-04
Volume: 9
Issue: 12
Pages: 2598
ISSN: 2073-4409 (ISSN-L)
DOI: 10.3390/cells9122598
PMC: PMC7761956
OpenAlex: W3109893680
Cited by: 133
References: 234
Citations by year: 2026: 17 · 2025: 27 · 2024: 23 · 2023: 24 · 2022: 24 · 2021: 18
FWCI: 1.71
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cells (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
Funders: AIRC (Associazione Italiana per la Ricerca sul Cancro) (IG21408)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: tumor hypoxia, metabolic reprogramming, chemoresistance, hypoxia-inducible factor, tumor microenvironment acidification, efflux pumps, cancer stemness, epithelial-mesenchymal transition, glycolysis, glutamine metabolism, oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, cancer metabolism
MeSH terms: Amino Acids, Animals, Hypoxia, Citric Acid Cycle, Glucose, Glutamine, Humans, Mitochondria, Neoplasms, Oxidation-Reduction, Oxidative Phosphorylation, Oxygen, Phenotype, Reactive Oxygen Species, Disease Progression, Drug Resistance, Neoplasm, Dimerization, Lactic Acid, Mice, Epithelial-Mesenchymal Transition, Tumor Microenvironment

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Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

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