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Cited by 94Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerViral Infectious Diseases and Gene Expression in Insects

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

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Kozlov, Alexandra M., Lone, Asad, Betts, Dean H., Cumming, Robert C.·2020·Scientific Reports
DOI 10.1038/s41598-020-65193-9PMC PMC7239882
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Abstract

Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the effect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the effect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fibroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fibroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. Furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. Our findings indicate that lactate preconditioning primes fibroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. Interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defined metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efficiency by amplifying a critical metabolic switch that occurs during iPSC generation.

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Authors
Kozlov, A. M., Lone, A., Betts, D. H., & Cumming, R. C.
Affiliations
Western University (CA)
Corresponding author
  • Betts, Dean H.
  • Cumming, Robert C.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-05-20
Volume
10
Issue
1
Pages
8388-8388
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-65193-9
PMC
PMC7239882
OpenAlex
W3027242253
Cited by
94
References
72
Citations by year
2026: 17 · 2025: 22 · 2024: 14 · 2023: 16 · 2022: 13 · 2021: 12
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Scholarship@Western (Western University) (submittedVersion)
  • Scholarship@Western (Western University) (submittedVersion, cc-by)
Funders
  • Ontario Institute for Regenerative Medicine
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2019-355803, rgpin-2019-04027, RGPIN-2019)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
HIF-1α stabilization, metabolic switch, oxidative phosphorylation, glycolysis, human dermal fibroblasts, reactive oxygen species, somatic cell reprogramming, c-Myc, SNAI1, iPSC generation
MeSH terms
Cells, Cultured, Diploidy, Fibroblasts, Glycolysis, Humans, Reactive Oxygen Species, Pyruvic Acid, Lactic Acid, Hypoxia-Inducible Factor 1, alpha Subunit

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