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Page 12 of 19 Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77

Figure 5. Glutamine metabolism. Thyroid cancer cells overexpress glutamine transporters and enzymes to fuel tumor progression. 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. Glutaminase; 2. Glutamate dehydrogenase; 3. Aspartate aminotransferase.

acid via Akt. Metformin, a pan-metabolic inhibitor, activates AMPK to inhibit mTOR1 and decrease blood
glucose and insulin levels. Metformin was effective at inhibiting PTC, FTC, and ATC growth in vitro and is
currently in a phase II clinical trial in combination with RAI for differentiated TC [31,147-149] .

MAPK signaling converges with PI3K signaling to regulate the expression and function of MYC and
HIF1A. Akt and mTORC1 upregulate MYC expression via enhancing translation [150-152] , and Akt signaling
also inhibits phosphorylation of MYC at thr58, preventing degradation [150,153] . MAPK signaling
phosphorylates MYC at ser62, extending the half-life [150,153] . PI3K and MAPK signaling both enhance HIF1A
expression through increased translation. MYC and HIF1A are considered the Warburg effect gatekeepers,
as both MYC and HIF1A are frequently overexpressed in TC and increase the expression of several rate-
limiting enzymes in glycolysis such as GLUTs, HK, PGK1, LDH, and MCTs as well as G6PDH and
GLS [18,50,151,152,154,155] . Unsurprisingly, nearly all of these genes are increased in PTC, FTC, and ATC, which
represent important steps for carbon flux through glycolysis and the PPP and nitrogen acquisition from
glutamine. This complex interplay between cell signaling and metabolism in cancer cells may be exploited
for strategic drug combinations that work against both oncogenic processes in aggressive TC.

CONCLUSION
Cancer cells must extensively reprogram metabolism for successful tumorigenesis. Rerouted metabolism is
essential for generating energy in the form of ATP, quenching ROS in the form of NADPH, generating
nucleotides de novo, forming adequate amino acid levels for protein and DNA synthesis, and storing carbon
in the form of fatty acids and glycogen. These pathways in cancer cell metabolism are attractive targets for