The emerging role and targetability of the TCA cycle in cancer metabolism

Abstract

The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

Keywords: cancer metabolism; glutaminolysis; glycolysis; the TCA cycle.

Figure 1

Transporters, fuels, enzymes, and biochemical reactions driving the TCA cycle. The typical input for the TCA cycle is acetyl-CoA, which is derived from pyruvate, the end product of glycolysis. Through a series of redox reactions, chemical bond energy from acetyl-CoA is harvested to produce high-energy electrons, which are carried to the electron transport chain by nicotinamide adenine dinucleotide (NAD⁺) and flavin adenine dinucleotide (FAD). Subsequent oxidative phosphorylation results in the production of adenosine triphosphate (ATP) from each acetyl-CoA. Because oxygen is required to regenerate NAD⁺ and FAD, the TCA cycle only proceeds in aerobic environments. There are a total of 8 steps in the TCA cycle, three of which are irreversible; the generation of citrate from oxaloacetate and acetyl-CoA by CS; the conversion of isocitrate to α-KG by IDH3; and the formation of succinyl-CoA from α-KG by KGDHC (Berg JM, ; Akram, 2014). The biochemical reactions in the TCA cycle are regulated by several means including substrate availability, product inhibition, and allosteric regulation, allowing the cell to control energy production based on its energy status (NADH/NAD⁺ ratio, ATP availability) and nutrient availability (Berg JM, 2002). Intermediates in the cycle can be derived from outside sources, such as the production of acetyl-CoA from β-oxidation of fatty acids or the production of α-KG from protein catabolism, particularly glutaminolysis (Houten and Wanders, ; Akram, 2014). Importantly, deregulation of TCA cycle enzymes, such as mutations and gene deregulations, or aberrant accumulation of TCA intermediates can have disease-relevant consequences. Proteins that are upregulated in cancer are highlighted as red and downregulated as blue, while enzymes mutated are marked with an asterisk. Abbreviations: CS: citrate synthase, AH: aconitase, IDH: isocitrate dehydrogenase, KGDHC: α-ketoglutarate dehydrogenase complex, OGDH: α-KG dehydrogenase, DLST: dihydrolipoamide S-succinyltransferase, DLD: dihydrolipoamide dehydrogenase, SCS: succinyl-CoA synthase, SDH: succinate dehydrogenase, FH: fumarate hydratase, MDH: malate dehydrogenase, PDH: pyruvate dehydrogenase, GLUT: glucose transporter, FATP: fatty acid transporter, SCL38A: sodium-coupled neutral amino acid transporter, ACLY: adenosine triphosphate citrate lyase, ACC: acetyl-CoA carboxylase, FAS: fatty acid synthase, GLS: glutaminase, GDH: glutamate dehydrogenase