Pyruvate Dehydrogenase and Pyruvate Dehydrogenase Kinase Expression in Non Small Cell Lung Cancer and Tumor-Associated Stroma
Open accessAbstract
Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however pyruvate is transformed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although, hypoxic intratumoral conditions account for HIF1alpha stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIF1alpha stabilization independently of hypoxia. In the present immunohistochemical study, we provide evidence that the PDH/PDK pathway is repressed in 73% of non small cell lung carcinomas, which may be a key reason for HIF1alpha stabilization and "aerobic glycolysis." However, about half of PDH-HIF pathway, and patients harboring these tumors have an excellent postoperative outcome. A small subgroup of clinically aggressive tumors maintains a coherent PDH and HIF/LDH5 expression. In contrast to cancer cells, fibroblasts in the tumor supporting stroma exhibit an intense PDH but reduced PDK1 expression favoring maximum PDH activity. This means that stroma may use lactic acid produced by tumor cells, preventing the creation of an intolerable intratumoral acidic environment at the same time.
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Pyruvate is converted to acetyl-CoA through mitochondrial pyruvate dehydrogenase (PDH), whereas acetate is transported into cells and converted to acetyl-CoA through acetyl-CoA synthase.
“Pyruvate is converted to acetyl-CoA through mitochondrial pyruvate dehydrogenase (PDH), whereas acetate is transported into cells and converted to acetyl-CoA through acetyl-CoA synthase (De Schrijver et al., 2003; Feron, 2009; Koukourakis et al., 2005; Pizer et al., 1996; Yoshimoto et al., 2001; Zaidi et al., 2012).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Koukourakis et al., 2005
Pyruvate or acetate can act as an alternative source to glucose and glutamine for lipid biosynthesis.
“pyruvate or acetate can act as an alternative source to glucose and glutamine for lipid biosynthesis.”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Koukourakis et al., 2005
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- Authors
- Koukourakis, M. I., Giatromanolaki, A., Sivridis, E., Gatter, K. C., & Harris, A. L.
- Affiliations
- Democritus University of Thrace (GR)
- John Radcliffe Hospital (GB)
- Cancer Research UK (GB)
- Corresponding author
- Koukourakis, Michael I.
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 7
- Issue
- 1
- Pages
- 1-6
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC1490315
- OpenAlex
- W1982107902
- Cited by
- 214
- References
- 20
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 13 · 2020: 16 · 2019: 9 · 2018: 14 · 2017: 8 · 2016: 11 · 2015: 13 · 2014: 13 · 2013: 6 · 2012: 11
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pyruvate dehydrogenase, pyruvate dehydrogenase kinase, non-small cell lung cancer, tumor stroma, HIF-1α, aerobic glycolysis, Warburg effect, LDH5, tumor hypoxia, cancer-associated fibroblasts, lactic acid, tumor acidosis, prognostic factors
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Autopsy, Carcinoma, Non-Small-Cell Lung, Fibroblasts, Humans, Immunohistochemistry, Ketone Oxidoreductases, Lung, Lung Neoplasms, Protein Kinases, Transcription Factors, Cell Hypoxia, Survival Rate, Stromal Cells, Protein Serine-Threonine Kinases, Lactic Acid, Hypoxia-Inducible Factor 1, alpha Subunit
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