Reprogramming of fatty acid metabolism in thyroid cancer: Potential targets and mechanisms

Abstract

Thyroid cancer (TC) is one of the most common endocrine system tumors, and its incidence continues to increase worldwide. Although most TC patients have a good prognosis, especially with continuous advancements in surgery, radioactive iodine therapy, chemotherapy, endocrine therapy and targeted therapy, the effectiveness of disease treatment has significantly improved. However, there are still some cases with a higher risk of death and greater aggressiveness. In these more challenging advanced or highly aggressive cases, tyrosine kinase inhibitors appear to be an effective treatment option. Unfortunately, these drugs are less than ideal in terms of efficacy because of their toxicity and potential for intrinsic or acquired resistance. Therefore, exploring new strategies targeting the metabolic characteristics of TC cells and overcoming drug resistance barriers in existing treatments have become key topics in the current field of TC research. In recent years, lipid metabolic reprogramming has gained attention as an important aspect of cancer development. Lipid metabolic reprogramming not only participates in the formation of the cell membrane structure, but also plays an important role in signal transduction and promoting cell proliferation. In particular, fatty acid (FA) metabolic reprogramming has attracted widespread attention and plays an important role in multiple aspects such as tumor growth, metastasis, enhanced invasive ability, immune escape, and drug resistance. Although TC is considered a disease that is highly dependent on specific types of metabolic activities, a comprehensive understanding of the specific mechanism of action of FA metabolic reprogramming in this process is lacking. This article aims to review how FA metabolic reprogramming participates in the occurrence and development of TC, focusing on the impact of abnormal FA metabolic pathways and changes in the expression and regulation of related genes over the course of this disease. By examining the complex interactions between FA metabolic disorders and carcinogenic signaling pathways in depth, we aim to identify new therapeutic targets and develop more precise and effective treatments for TC.

Keywords: Thyroid cancer; fatty acid metabolic reprogramming; lipid metabolism; mechanism; target.

Figure 1

FA metabolism in TC. As a transcriptional regulator, SREBP1 participates in the progression of TC by regulating the expression of key downstream enzymes such as ACLY, ACC, FASN, and SCD1. In TC, SREBP1 promotes TC progression and enhances invasion by promoting the Hippo-YAP, PI3K-AKT/mTOR, and ILK/AKT/mTOR signaling pathways, and FASN promotes the c-Met-PI3K-AKT signaling pathway. CircPCNXL2 promotes the proliferation of TC cells by increasing ACC expression, and SNHG can promote the proliferation of TC cells by increasing ACSL1 expression. Fatostatin (an SREBP1 inhibitor), NDI-091143 and SB-204990 (ACLY inhibitors), C75, EGCG, quercetin, and curcumin (FASN inhibitors), MF-438 and A939572 (SCD1 inhibitors), and etomoxir and perhexiline (CPT1 inhibitors) can inhibit the progression of TC. FA, fatty acid; TC, thyroid cancer; SREBP1, sterol regulatory element-binding protein 1; ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; ACSL1, long-chain acyl-CoA synthetase 1; CPT1, carnitine palmitoyl transferase 1; FAO, fatty acid oxidation; TCA, tricarboxylic acid cycle; PUFA, polyunsaturated fatty acid; MUFA, monounsaturated fatty acid.

Figure 2

Abnormal FA intake in TC and its biological effects. CD36 can promote the PI3K-AKT pathway, and FATP can promote the c-MYC and MAPK/C-FOS pathways and increase the intake of exogenous FAs, thus providing energy sources for the invasion of TC. FABP can promote the progression of TC by inhibiting the expression of genes such as BCL2 and PTEN. FA, fatty acid; TC, thyroid cancer; FABP, FA binding protein; FATP, FA transport protein.

Figure 3

Other relevant FA metabolism targets in TC. CD147 can downregulate CPT1A by downregulating PPARα expression. Moreover, inhibiting AMPK activity can also downregulate CPT1A, which together leads to limited tumor growth. In addition, decreased AMPK activity and increased CD147 and LDLR activities can jointly promote the expression of downstream SREBP1, FASN, ACLY, and ACC, thereby promoting tumor growth, metastasis, and drug resistance. FA, fatty acid; TC, thyroid cancer; AMPK, AMP-activated protein kinase; LDLR, low-density lipoprotein receptor; PPARγ, peroxisome proliferator-activated receptor γ.