Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
Current drug development in oncology is non-selective as it typically focuses on pathways essential for the survival of all dividing cells. The unique metabolic profile of cancer, which is characterized by increased glycolysis and suppressed mitochondrial glucose oxidation (GO) provides cancer cells with a proliferative advantage, conducive with apoptosis resistance and even increased angiogenesis. Recent evidence suggests that targeting the cancer-specific metabolic and mitochondrial remodeling may offer selectivity in cancer treatment. Pyruvate dehydrogenase kinase (PDK) is a mitochondrial enzyme that is activated in a variety of cancers and results in the selective inhibition of pyruvate dehydrogenase, a complex of enzymes that converts cytosolic pyruvate to mitochondrial acetyl-CoA, the substrate for the Krebs’ cycle. Inhibition of PDK with either small interfering RNAs or the orphan drug dichloroacetate (DCA) shifts the metabolism of cancer cells from glycolysis to GO and reverses the suppression of mitochondria-dependent apoptosis. In addition, this therapeutic strategy increases the production of diffusible Krebs’ cycle intermediates and mitochondria-derived reactive oxygen species, activating p53 or inhibiting pro-proliferative and pro-angiogenic transcription factors like nuclear factor of activated T cells and hypoxia-inducible factor 1α. These effects result in decreased tumor growth and angiogenesis in a variety of cancers with high selectivity. In a small but mechanistic clinical trial in patients with glioblastoma, a highly aggressive and vascular form of brain cancer, DCA decreased tumor angiogenesis and tumor growth, suggesting that metabolic-targeting therapies can be translated directly to patients. More recently, the M2 isoform of pyruvate kinase (PKM2), which is highly expressed in cancer, is associated with suppressed mitochondrial function. Similar to DCA, activation of PKM2 in many cancers results in increased mitochondrial function and decreased tumor growth. Therefore, reversing the mitochondrial suppression with metabolic-modulating drugs, like PDK inhibitors or PKM2 activators holds promise in the rapidly expanding field of metabolic oncology.
Keywords: mitochondria, tumor metabolism, dichloroacetate, pyruvate dehydrogenase kinase, hypoxia-inducible factor 1α, apoptosis resistance
Citation: Sutendra G and Michelakis ED (2013) Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front. Oncol. 3:38. doi: 10.3389/fonc.2013.00038
Received: 12 December 2012; Paper pending published: 31 December 2012;
Accepted: 11 February 2013; Published online: 07 March 2013.
Edited by:Catherine Brenner, Institut National de la Santé et de la Recherche Médicale-University of Paris Sud, France
Reviewed by:Mariusz R. Wieckowski, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland
Hilary Ann Coller, Princeton University, USA
Copyright: © 2013 Sutendra and Michelakis. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Evangelos D. Michelakis, Department of Medicine, University of Alberta, 2C2 Walter Mackenzie Center, 8440 112st NW, Edmonton, AB, Canada T6G 2B7. e-mail: firstname.lastname@example.org