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Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77 Page 7 of 19

Figure 2. The pentose phosphate pathway. The pentose phosphate pathway is highly active in thyroid cancer. Bold arrows indicate
increased metabolite flux. Beige circles indicate enzymes not shown to be aberrantly expressed in TC. Red circles display overexpressed
enzymes in TC. Inhibitors are outlined in red circles with conjoining red inhibitor (T) bars. Inhibitors in bold have demonstrated efficacy
in TC models. Enzyme key: 1. Glucose-6-phosphate dehydrogenase; 2. 6-Phosphogluconolactonase; 3. 6-Phosphogluconate
dehydrogenase; 4. Ribose-5-phosphate isomerase; 5. Ribulose-5-phosphate 3-epimerase; 6. Transketolase; 7. Transaldolase.

mitochondria via mitochondrial pyruvate carrier 1 and 2 . High concentrations of NAD+, PEP, and
[81]
pyruvate encourage the dehydrogenation to acetyl-CoA via pyruvate dehydrogenase (PDH) [15,35] . Along with
acetyl-CoA, PDH forms another molecule of NADH from NAD+. The acetyl-CoA is then able to progress
in the TCA cycle [15,35] . In reality, this reaction does not occur at an appreciable rate in cancer cells due to the
rare instance of the cell having a high NAD+/NADH ratio . Instead, mitochondrial pyruvate is more likely
[82]
to be irreversibly converted to oxaloacetic acetate (OAA) via pyruvate carboxylase, which requires ATP and
[83]
bicarbonate . OAA may be used to refuel the TCA cycle if mutations in isocitrate dehydrogenase or
succinate dehydrogenase cause a broken TCA cycle [Figure 3] . In some cancers, the mitochondrial
[83]
isoform of PEP carboxykinase (PEPCK) converts OAA to PEP for transport to the cytoplasm via the
mitochondrial citrate carrier (CIC) . This is the only method for a cell to convert pyruvate back to PEP for
[84]
gluconeogenesis [15,35] .

Interestingly, Vincent et al. reported that out of several types of solid tumors they investigated, PTC
[84]
samples had the highest expression of PEPCK, and 3-Mercaptopropionic acid inhibited PEPCK in lung
cancer cells. Despite this observation, PEPCK inhibition remains an unexplored target in TC. Finally, CIC is
overexpressed in PTC and ATC, at least in part through dysregulation in a lncRNA-miRNA axis . ShRNA
[85]
targeted against CIC resulted in reduced PTC and ATC cell migration in vitro .
[85]
THE TCA CYCLE
In cancer cells, the TCA cycle serves as a hub for anaplerosis and fatty acid metabolism, often being co-
opted by overexpression or mutations of key enzymes to fuel cancer progression. Citrate is formed from
OAA and acetyl-CoA via citrate synthase. Citrate can be converted to isocitrate via aconitase and then to
alpha ketoglutarate (αKG) via isocitrate dehydrogenase (IDH) [15,35] . However, isozymes of IDH are
frequently mutated in several cancers, causing the first stall in the TCA cycle [86-88] . IDH mutations form the
oncometabolite 2-hydroxyglutarate (2-HG) at higher rates than wildtype IDH, which competitively inhibits
several nuclear proteins such as histone and RNA demethylases and DNA methylation and repair