Reprogramming of Thyroid Cancer Metabolism: from Mechanism to Therapeutic Strategy

Abstract

Thyroid cancer as one of the most prevalent malignancies of endocrine system, has raised public concern and more research on its mechanism and treatment. And metabolism-based therapies have advanced rapidly, for the exclusive metabolic profiling of thyroid cancer. In thyroid cancer cells, plenty of metabolic pathways are reprogrammed to accommodate tumor microenvironment. In this review, we initiatively summarize recent progress in the full-scale thyroid cancer metabolic rewiring and the interconnection of various metabolites. We also discuss the efficacy and prospect of metabolic targeted detection as well as therapy. Comprehending metabolic mechanism and characteristics of thyroid cancer roundly will be highly beneficial to managing individual patients.

Keywords: Carcinogenesis; Diagnosis; Genetics; Metabolism; Targeted therapy; Thyroid cancer.

Fig. 1

Overview of metabolic intersections in TC cells. The metabolic pathways in TC cells have an intricate interplay of intermediate products, metabolites and enzymes. By this closely connection covering glycolysis, PPP, one-carbon metabolism, the TCA cycle, lipid and amino acid metabolism and others, TC cells are able to optimize the holistic metabolic pattern to the maximum extent. The TCA cycle as the center of cell metabolism, mutates significantly for faster energy production. Since quite more lactate molecules are generated, the peculiar lactate shuttle is established, transmitting fresh fuel supply to the neighboring TC cells. With this subtle design, TC can progress rapidly. Abbreviations (not mentioned in the text): 3-PG, 3-phosphoglycerate; Ser, serine; OAA, oxaloacetate; α-KG, α-ketoglutarate; Asp, aspartate; Glu, glutamic acid; Gln, glutamate

Fig. 2

Glucose metabolism in TC

Fig. 3

Lipid metabolism in TC. To properly utilize FAs of different chain lengths, TC cells redistribute carriers with their respective capabilities. With the aim of replenishing energy supply approaches, the upregulated CPT1 transports more FA-generated acyl-CoA into the mitochondrion, and subsequently performs FAO and enters the TCA cycle, not wasting any component of a cell. And citrate from the TCA cycle can be translocated to the cytoplasm and then generate considerable cholesterol, TG and phospholipid, which are essentials in TC cells. Abbreviations: ACAT, cholesterol acyltransferase; HMGCS, 3-hydroxy-3-methylglutaryl-CoA synthase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase

Fig. 4

Amino acid and nucleotide metabolism in TC. Amino acids as constituents of proteins and materials of nucleotides, play an important part in linking metabolism of different substances. By regulating activities of multiple enzymes, TC cells reach a status where biosynthesis is far beyond sufficient, allowing rapid proliferation and metastasis.Abbreviations: PSAT, phosphoserine amino transferase; PSPH, phosphoserine phosphatase; THF, tetrahydrofolate; AMT, aminomethyltransferase; DLD, dihydrolipoamide dehydrogenase; GCSH, glycine cleavage system protein H; Asn, asparagine; ASNS, asparagine synthase; GLUL, glutamate-ammonia ligase; Gly, glycine; Met, methionine; Hcy, homocysteine; Cys, cysteine; GSHS, glutathione synthase; ACL, ATP citrate lyase; GOT, glutamate oxaloacetate transaminase; P5C, pyrroline 5-carboxylate; Pro, proline; PRODH, proline dehydrogenase

Fig. 5

Therapeutic strategies of TC