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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Henriques, Jeremy Tsang, Tsz Mon Harris, Robert A. Halim, Nader D. Zhou, Shaoyu Wu, Hong Schell, Michael J. Mcfate, Thomas Thakar, Jay Teahan, Orla Mohyeldin, Ahmed Jeoung, Nam Ho Verma, Ajay Lu, Huasheng Califano, Joseph A. |
| Description | Author Affiliation: McFate T ( Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.) |
| Abstract | 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 33 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-08-15 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Head And Neck Neoplasms Enzymology Pyruvate Dehydrogenase Complex Metabolism Cell Division Cell Nucleus Cell Survival Cytosol Glycolysis Pathology Hypoxia-Inducible Factor 1, Alpha Subunit Kinetics Neoplasm Invasiveness Antagonists & Inhibitors Tumor Cells, Cultured Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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