The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents

Abstract

Cancer cells exhibit an altered metabolism which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. This provides anabolic support and selective growth advantage for cancer cells. Recently, a new concept has arisen suggesting that these metabolic changes may be due, in part, to an attenuated mitochondrial function which results from the inhibition of the pyruvate dehydrogenase complex (PDC). This mitochondrial complex links glycolysis to the Krebs cycle and the current understanding of its regulation involves the cyclic phosphorylation and dephosphorylation by specific pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs).Here we review literature pertinent to provide an overview of the multiple levels of PDC regulation to allow cancer cells to adapt their metabolism to their bioenergetic demands. In particular, new post-translational modifications, such as phosphorylation, acetylation or succinylation of different PDC components have been highlighted and could act in a concerted manner to provide a high metabolic flexibility. In addition, we presented recent studies that underline the role of PDC in the control of cancer cell proliferation and metastasis.Finally, the therapeutic potential of PDK inhibitors is quickly regaining a forefront position in cancer. Several studies have shown that the decline in PDK activity either by pharmacological inhibition or a decreased expression leading to an enhanced PDC activity is associated with a reduction in tumor growth in vivo. The current understanding of properties of different inhibitors targeting PDKs which could have potential therapeutic effects in different types of cancer is presented.The mitochondrial pyruvate dehydrogenase complex (PDC) acts as a gatekeeper enzyme for energy metabolism by catalyzing irreversible decarboxylation of pyruvate into acetyl-CoA. The activity of PDC is highly regulated, at least in part, by reversible phosphorylation through pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs) the functions of which are regulated by cellular nutrient cues. Here, we provide an overview of the complexities and peculiarities in the regulation of PDC for the control of substrate metabolism and flexibility in cancer cells. Particular attention is devoted to newly identified posttranslational modifications, such as phosphorylation, acetylation or succinylation, of the different PDC components and the mechanisms by which these modifications may act in concert to provide an optimal metabolic adaptation to sustain energy demands in cancer cells. We also discuss new pharmacological approaches used to develop effective PDK inhibitors as well as the properties and potential usefulness of these inhibitors for complex human diseases such as cancer. The Pyruvate Dehydrogenase Complex: A Crucial Role in the Regulation of Energy MetabolismThe multi-subunit mitochondrial PDC is at the center of glucose oxidative metabolism. PDC inserts pyruvate into the t...

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…However, DCA suffers from some drawbacks as a therapeutic agent, such as low potency/selectivity and poor pharmacokinetics (91). The potential of PDK family members as therapeutic targets has prompted considerable interest in developing specific inhibitors against these enzymes (91)(92)(93).…”

Metabolic Plasticity of Tumor Cell Mitochondria

“…The consequent boost of kinase signaling pathways (144) affects mitochondrial metabolism, e.g. by tyrosine kinases that inhibit at multiple levels the PDC (145). In addition, many mitochondrial FAO enzymes contain ROS-sensitive Cys residues (Figure 5).…”

Pyruvate dehydrogenase B promoted the growth and migration of the nasopharyngeal carcinoma cells

“…Dysregulation of PDH has been reported in various cancer types [5,7,8]. The expression of PDH is an independent prognostic factor for gastric cancer, and the positive expression of PDH is predictive for the favorable outcome.…”

“…Pyruvate dehydrogenase B (PDHB) localizes in the mitochondrial and consists of multiple subunits [5]. PDHB catalyzes the glucose-derived pyruvate to the acetyl-CoA and plays important roles in oxidative phosphorylation [5]. In cancer cells, PDH is phosphorylated by pyruvate dehydrogenase kinase (PDK), which inhibits the activity of PDH [6].…”

“…Pyruvate dehydrogenase B (PDHB) localizes in the mitochondrial and consists of multiple subunits [5]. PDHB catalyzes the glucose-derived pyruvate to the acetyl-CoA and plays important roles in oxidative phosphorylation [5].…”