Brain Tumor Res Treat.  2013 Oct;1(2):57-63. 10.14791/btrt.2013.1.2.57.

Pyruvate Dehydrogenase Kinase as a Potential Therapeutic Target for Malignant Gliomas

• Jha MK
• Suk K

• KMID: 2048476
• DOI: http://doi.org/10.14791/btrt.2013.1.2.57

Abstract

Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hallmarks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in gliomas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic approach for the treatment of malignant gliomas.

Keyword

Pyruvate dehydrogenase kinase; Glioma; Gliomagenesis; Dichloroacetate; Hypoxia-inducible factor

MeSH Terms

Amino Acids
Decarboxylation
Dichloroacetic Acid
Fatty Acids
Glioma*
Glycolysis
Lactic Acid
Metabolic Networks and Pathways
Nucleotides
Oxidoreductases*
Oxygen
Phosphotransferases*
Pyruvic Acid*
Amino Acids
Fatty Acids
Lactic Acid
Nucleotides
Oxidoreductases
Oxygen
Phosphotransferases
Pyruvic Acid

Figure

• 

  Fig. 1 Classification of gliomas based on the origin of the cells. Adult neural stem cells and multipotent progenitors differentiate into mature neurons, astrocytes and oligodendrocytes. Neural stem cells and different types of progenitor cells can form gliomas. Mature astrocytes and oligodendrocytes also serve as cells of origin for gliomas.

• 

  Fig. 2 Potential role played by PDKs in malignant gliomas. Glucose entering the cell is metabolized by glycolysis to pyruvate. Most of the pyruvate in non-cancerous cells enters the mitochondria under aerobic conditions and a small fraction is metabolized to lactate. PDH in mitochondria converts pyruvate into acetyl-CoA, which enters the TCA cycle. On the other hand, in glioma cells, the oxidative (mitochondrial) pathway of glucose utilization is suppressed, and most of the pyruvate is converted into lactate. Hence, the relative activities of LDH and PDH determine the fate of pyruvate. PDK, which can be inhibited by DCA, inhibits PDH through phosphorylation and regulates its activities. HIF-1 induces PDK, which inactivates PDH resulting in suppression of the TCA cycle and mitochondrial respiration. Moreover, HIF-1 also stimulates glycolysis and the expression of LDH, thereby facilitating the conversion of pyruvate into lactate. DCA: dichloroacetate, HIF: hypoxia-inducible factor, LDH: lactate dehydrogenase, PDH: pyruvate dehydrogenase, PDK: pyruvate dehydrogenase kinase, TCA: tricarboxylic acid.

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