HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there...

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Published inCells (Basel, Switzerland) Vol. 10; no. 9; p. 2371
Main Authors Lee, Shen-Han, Golinska, Monika, Griffiths, John R.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 09.09.2021
MDPI
Subjects
1-Phosphatidylinositol 3-kinase
Adenosine triphosphate
AKT protein
AMP-activated protein kinase
Angiogenesis
Autophagy
Binding sites
Cancer
cancer metabolism
Carbohydrate metabolism
Clinical trials
Creatine
creatine metabolism
Dehydrogenases
Drug resistance
Enzymes
Epigenetics
Genomics
Glucose
Glucose metabolism
Glutamine
glycolysis
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-inducible factor 1a
hypoxia-inducible factor-1 (HIF-1)
Kinases
Lipid metabolism
Metabolism
Metastasis
Microenvironments
Myc
Myc protein
Phosphorylation
Post-translation
Protein turnover
Review
Signal transduction
Solid tumors
Transcription factors
Tumors
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Abstract In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
AbstractList In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
Author Lee, Shen-Han
Griffiths, John R.
Golinska, Monika
AuthorAffiliation 3 Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK
1 Department of Otorhinolaryngology, Hospital Sultanah Bahiyah, KM6 Jalan Langgar, Alor Setar 05460, Kedah, Malaysia
2 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; monika.golinska@cruk.cam.ac.uk (M.G.); john.griffiths@cruk.cam.ac.uk (J.R.G.)
AuthorAffiliation_xml – name: 3 Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK
– name: 1 Department of Otorhinolaryngology, Hospital Sultanah Bahiyah, KM6 Jalan Langgar, Alor Setar 05460, Kedah, Malaysia
– name: 2 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; monika.golinska@cruk.cam.ac.uk (M.G.); john.griffiths@cruk.cam.ac.uk (J.R.G.)
Author_xml – sequence: 1
  givenname: Shen-Han
  orcidid: 0000-0002-6147-2963
  surname: Lee
  fullname: Lee, Shen-Han
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  givenname: Monika
  surname: Golinska
  fullname: Golinska, Monika
– sequence: 3
  givenname: John R.
  orcidid: 0000-0001-7369-6836
  surname: Griffiths
  fullname: Griffiths, John R.
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Snippet In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor,...
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SubjectTerms 1-Phosphatidylinositol 3-kinase
Adenosine triphosphate
AKT protein
AMP-activated protein kinase
Angiogenesis
Autophagy
Binding sites
Cancer
cancer metabolism
Carbohydrate metabolism
Clinical trials
Creatine
creatine metabolism
Dehydrogenases
Drug resistance
Enzymes
Epigenetics
Genomics
Glucose
Glucose metabolism
Glutamine
glycolysis
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-inducible factor 1a
hypoxia-inducible factor-1 (HIF-1)
Kinases
Lipid metabolism
Metabolism
Metastasis
Microenvironments
Myc
Myc protein
Phosphorylation
Post-translation
Protein turnover
Review
Signal transduction
Solid tumors
Transcription factors
Tumors
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Title HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
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https://pubmed.ncbi.nlm.nih.gov/PMC8472468
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Volume 10
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