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

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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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Figure 1 Metabolic rewiring induced by hypoxia. (A) In normoxic tumor areas, glucose taken up by glucose transporter 1 (GLUT1) and transformed by glycolysis into pyruvate is mainly oxidized into Acetyl-Coenzyme A (AcCoA) by pyruvate dehydrogenase (PDH), fueling the tricarboxylic acid (TCA) cycle and the electron transport chain to produce ATP. By contrast, lactic fermentation is low. Fatty acid (FAs) oxidation (FAO) prevails over FA and triglyceride (TG) synthesis, further producing AcCoA entering the TCA cycle. The oxidative metabolism of glutamine (Gln) is a third anaplerotic pathway of TCA cycle. (B) Hypoxia enhances glucose uptake via GLUT1 and metabolism into lactate, thanks to the hypoxia-inducible factor (HIF)-1α-dependent upregulation of glycolytic enzymes, lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 that inhibits PDH. In this way, cancer cells produce huge amounts of lactate, exported by the hypoxia-sensitive gene mono-carboxylate transporter 4 (MCT4) and H+, buffered by other HIF-1α-targeted genes, such as carbonic anhydrase (CA) IX and XII. Part of lactate can enter the mitochondria via MCT, and is transformed into pyruvate by mitochondrial LDH, fueling TCA cycle. Notwithstanding such anaplerosis, TCA and electron transport chain (ETC) are reduced in hypoxic tumors that aberrantly reduce O2 into reactive oxygen species (ROS). Amino acids (AAs) uptake is increased thanks to the upregulation of xCT and L-type amino acid transporter 1 (LAT1), also induced by HIF-1α. The catabolism of Gln and glutamate (Glu), however, not only fuels TCA cycle, since it is mainly used to synthesize glutathione (GSH) or produce α-ketoglutarate (αKG) that is reduced into citrate and NADPH via the reductive glutamine metabolism, providing carbons for FA and triglycerides (TGs) synthesis. Dotted arrows: down-modulated metabolic pathways; solid arrows: up-regulated metabolic pathways.
Figure 1 Metabolic rewiring induced by hypoxia. (A) In normoxic tumor areas, glucose taken up by glucose transporter 1 (GLUT1) and transformed by glycolysis into pyruvate is mainly oxidized into Acetyl-Coenzyme A (AcCoA) by pyruvate dehydrogenase (PDH), fueling the tricarboxylic acid (TCA) cycle and the electron transport chain to produce ATP. By contrast, lactic fermentation is low. Fatty acid (FAs) oxidation (FAO) prevails over FA and triglyceride (TG) synthesis, further producing AcCoA entering the TCA cycle. The oxidative metabolism of glutamine (Gln) is a third anaplerotic pathway of TCA cycle. (B) Hypoxia enhances glucose uptake via GLUT1 and metabolism into lactate, thanks to the hypoxia-inducible factor (HIF)-1α-dependent upregulation of glycolytic enzymes, lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 that inhibits PDH. In this way, cancer cells produce huge amounts of lactate, exported by the hypoxia-sensitive gene mono-carboxylate transporter 4 (MCT4) and H+, buffered by other HIF-1α-targeted genes, such as carbonic anhydrase (CA) IX and XII. Part of lactate can enter the mitochondria via MCT, and is transformed into pyruvate by mitochondrial LDH, fueling TCA cycle. Notwithstanding such anaplerosis, TCA and electron transport chain (ETC) are reduced in hypoxic tumors that aberrantly reduce O2 into reactive oxygen species (ROS). Amino acids (AAs) uptake is increased thanks to the upregulation of xCT and L-type amino acid transporter 1 (LAT1), also induced by HIF-1α. The catabolism of Gln and glutamate (Glu), however, not only fuels TCA cycle, since it is mainly used to synthesize glutathione (GSH) or produce α-ketoglutarate (αKG) that is reduced into citrate and NADPH via the reductive glutamine metabolism, providing carbons for FA and triglycerides (TGs) synthesis. Dotted arrows: down-modulated metabolic pathways; solid arrows: up-regulated metabolic pathways.CC BY · PubMed Central
Figure 2 Metabolism-independent factors determining chemoresistance in hypoxia. HIF-1α transcriptionally induces drug efflux transporters belonging to the adenosine triphosphate (ATP) Binding Cassette (ABC) family, such as ABC transporter B1/multidrug resistance 1 (ABCB1/MDR1, known as P-glycoprotein/Pgp), ABC transporter G2/breast cancer resistance protein (ABCG2/BCRP), lung cancer resistance protein (LRP), ABC transporter C1/multi-drugs resistance related protein 1 (ABCC1/MRP1), by cooperating with the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) that also up-regulates anti-oxidant enzymes. Moreover, HIF-1α increases genes that induce the acquisition of a pro-invasive and stem-like phenotype, such as matrix metalloprotease 9 (MMP9), C-X-C chemokine receptor type 4 (CXCR4), osteopontin, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF), and up-regulates genes promoting DNA repair, such as topoisomerase 2A (TOP2A), DNA-protein kinases (DNA-PKs), Ku-70, and Ku-80, inhibits TP53 activity, preventing DNA damage. This complex and coordinated transcriptional program favors cell survival and determines chemoresistance in cancer cells.
Figure 2 Metabolism-independent factors determining chemoresistance in hypoxia. HIF-1α transcriptionally induces drug efflux transporters belonging to the adenosine triphosphate (ATP) Binding Cassette (ABC) family, such as ABC transporter B1/multidrug resistance 1 (ABCB1/MDR1, known as P-glycoprotein/Pgp), ABC transporter G2/breast cancer resistance protein (ABCG2/BCRP), lung cancer resistance protein (LRP), ABC transporter C1/multi-drugs resistance related protein 1 (ABCC1/MRP1), by cooperating with the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) that also up-regulates anti-oxidant enzymes. Moreover, HIF-1α increases genes that induce the acquisition of a pro-invasive and stem-like phenotype, such as matrix metalloprotease 9 (MMP9), C-X-C chemokine receptor type 4 (CXCR4), osteopontin, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF), and up-regulates genes promoting DNA repair, such as topoisomerase 2A (TOP2A), DNA-protein kinases (DNA-PKs), Ku-70, and Ku-80, inhibits TP53 activity, preventing DNA damage. This complex and coordinated transcriptional program favors cell survival and determines chemoresistance in cancer cells.CC BY · PubMed Central
Figure 3 Metabolism-dependent factors inducing chemoresistance in hypoxia and possible therapeutic strategies. In hypoxic tumor areas, HIF-1α increases glucose uptake and anaerobic glycolysis, thanks to the upregulation of glucose transporter 1 (GLUT1), hexokinase II (HKII), phosphofructokinase 2/phosphofructokinase binding protein 3 (PFK2/PFKBP3), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDH-A), with consequent export of lactate and H+ via monocarboxylate transporter 4 (MCT4). The decreased extracellular pH inactivates chemotherapeutic drugs, such as anthracyclines, and is compensated by the Na+/H+ exchanger (NHE) and by the carbonic anhydrase (CA) IX and XII. These enzymes create a slightly alkaline pH in the plasma membrane, which is optimal for the catalytic efficiency of ATP binding cassette transporter B1/P-glycoprotein (ABCB1/Pgp). Part of lactate may enter in the mitochondria via MCT and be transformed into pyruvate by a mitochondrial LDH isoform. Pyruvate is imported in mitochondria by the mitochondrial pyruvate carrier (MPC), but the low activity of pyruvate dehydrogenase (PDH) produced by the HIF-1α-driven upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and the consume of Acetyl Coenzyme A (AcCoA) by fatty acid (FA) synthase (FASN) reduce the metabolic flow through the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation (OXPHOS). The reduced mitochondrial metabolism, coupled with increased mitophagy and compensatory mitogenesis promoted by HIF-1α, results in paradoxically high levels of ATP, which supports the catalytic activity of ABC transporters, increasing the efflux of multiple chemotherapeutic drugs. This wide metabolic rewiring induces chemoresistance but it can be counteracted by metabolic modifiers inhibiting specific enzymes (indicated in red). Abbreviations: 2-DG: 2-deoxy-D-glucose; 3BrPyr: 3-Bromo-pyruvate; EIPA: ethyl-isopropyl amiloride; DCA: dichloroacetate; mito-CP: mitochondria-targeted carboxy-proxyl nitroxide; TPP+: triphenyl alkyl phosphonium; mito-DCA: mitochondria-targeted dichloroacetate; mito-metformin: mitochondria-targeted metformin.
Figure 3 Metabolism-dependent factors inducing chemoresistance in hypoxia and possible therapeutic strategies. In hypoxic tumor areas, HIF-1α increases glucose uptake and anaerobic glycolysis, thanks to the upregulation of glucose transporter 1 (GLUT1), hexokinase II (HKII), phosphofructokinase 2/phosphofructokinase binding protein 3 (PFK2/PFKBP3), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDH-A), with consequent export of lactate and H+ via monocarboxylate transporter 4 (MCT4). The decreased extracellular pH inactivates chemotherapeutic drugs, such as anthracyclines, and is compensated by the Na+/H+ exchanger (NHE) and by the carbonic anhydrase (CA) IX and XII. These enzymes create a slightly alkaline pH in the plasma membrane, which is optimal for the catalytic efficiency of ATP binding cassette transporter B1/P-glycoprotein (ABCB1/Pgp). Part of lactate may enter in the mitochondria via MCT and be transformed into pyruvate by a mitochondrial LDH isoform. Pyruvate is imported in mitochondria by the mitochondrial pyruvate carrier (MPC), but the low activity of pyruvate dehydrogenase (PDH) produced by the HIF-1α-driven upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and the consume of Acetyl Coenzyme A (AcCoA) by fatty acid (FA) synthase (FASN) reduce the metabolic flow through the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation (OXPHOS). The reduced mitochondrial metabolism, coupled with increased mitophagy and compensatory mitogenesis promoted by HIF-1α, results in paradoxically high levels of ATP, which supports the catalytic activity of ABC transporters, increasing the efflux of multiple chemotherapeutic drugs. This wide metabolic rewiring induces chemoresistance but it can be counteracted by metabolic modifiers inhibiting specific enzymes (indicated in red). Abbreviations: 2-DG: 2-deoxy-D-glucose; 3BrPyr: 3-Bromo-pyruvate; EIPA: ethyl-isopropyl amiloride; DCA: dichloroacetate; mito-CP: mitochondria-targeted carboxy-proxyl nitroxide; TPP+: triphenyl alkyl phosphonium; mito-DCA: mitochondria-targeted dichloroacetate; mito-metformin: mitochondria-targeted metformin.CC BY · PubMed Central

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Metadata

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
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
Licence
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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