The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells
Open accessAbstract
High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha (PDHalpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHalpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.
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Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
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Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108
p53 Regulates Mitochondrial Respiration
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Akt Stimulates Aerobic Glycolysis in Cancer Cells
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Cited by
Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057
Hypoxia, HIF1 and glucose metabolism in the solid tumour
Denko, N. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2468 · Cited by 1,707
HIF-1: upstream and downstream of cancer metabolism
Semenza, G. L. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.10.009 · Cited by 1,372
Acidic extracellular microenvironment and cancer
Kato, Y., Ozawa, S., Miyamoto, C., Maehata, Y., Suzuki, A., Maeda, T., & Baba, Y. (2013) · Cancer Cell International · doi:10.1186/1475-2867-13-89 · Cited by 1,300
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Metadata
- Authors
- McFate, T., Mohyeldin, A., Lu, H., Thakar, J., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsang, T. M., Teahan, O., Zhou, S., Califano, J. A., Jeoung, N. H., Harris, R. A., & Verma, A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 283
- Issue
- 33
- Pages
- 22700-22708
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2058691572
- Cited by
- 385
- References
- 13
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- McFate, T., Mohyeldin, A., Lu, H., Thakar, J., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsang, T. M., Teahan, O., Zhou, S., Califano, J. A., Jeoung, N. H., Harris, R. A., & Verma, A. (2008). Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m801765200
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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