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Cited by 32Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerDrug Transport and Resistance Mechanisms

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Autoregulation of H(+)/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production

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Blaszczak, Wiktoria, Williams, Hannah, Swietach, Pawel·2022·British Journal of Cancer
DOI 10.1038/s41416-022-01910-7PMC PMC9519749
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Abstract

Background: Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production. Methods: Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; P HLac) and lactic acid production (inferred from H+ and lactate excretion; J HLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype. Results: MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce J HLac because of a compensatory increase in the transmembrane [lactate] driving force. J HLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced J HLac but this was via cytoplasmic acidification blocking glycolytic enzymes. Conclusions: We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.

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Metadata

Authors
Blaszczak, W., Williams, H., & Swietach, P.
Affiliations
University of Oxford (GB)
Corresponding author
Swietach, Pawel
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2022-07-15
Volume
127
Issue
7
Pages
1365-1377
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/s41416-022-01910-7
PMC
PMC9519749
OpenAlex
W4285591986
Cited by
32
References
4
Citations by year
2026: 5 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 1
FWCI
2.84
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • University of Oxford
  • Horizon 2020 Framework Programme (MSCA‐ITN‐2018, H2020-MSCA, 813834, H2020-MSCA-ITN-2018, H2020-MSCA-ITN)
  • H2020 European Research Council (723997)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
monocarboxylate transporters, autoregulation, lactic acid production, glycolysis, pancreatic ductal adenocarcinoma, cytoplasmic acidification, extracellular acidity, membrane permeability, cancer metabolism
MeSH terms
Glycolysis, Homeostasis, Humans, Pancreatic Neoplasms, Lactic Acid, Monocarboxylic Acid Transporters

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