The role of Wnt signaling pathway in tumor metabolic reprogramming

Abstract

The occurrence and development of tumors is a complex process involving long-term multi-factor participation. In this process, tumor cells from a set of abnormal metabolic patterns that are different from normal cells. This abnormal metabolic change is called metabolic reprogramming of tumors. Wnt signaling pathway is one of the critical signaling pathways regulating cell proliferation and differentiation. In recent years, it has been found that Wnt signaling participates in the occurrence and development of malignant tumors by affecting metabolic reprogramming. This paper reviews the role of Wnt signaling in tumor metabolic reprogramming to provide crucial theoretical guidance for targeted therapy and drug response of tumors.

Keywords: Wnt signaling; targeted therapy; tumor metabolic reprogramming.

Figure 1

metabolic pathways in cancer cells. Highly proliferating cells promote glucose catabolism and glutamine catabolism by regulating key metabolic pathways, driving molecular synthesis and maintaining energy balance through molecular interactions. Cancer cells use aerobic glycolysis to produce ATP and promote pyruvate synthesis to promote glycolysis by increasing the expression of glycolytic enzymes. Tumor cells also produce macromolecules such as NADPH and 5-carbon sugar-driven nucleic acids via the pentose phosphate pathway. The citrate from the TCA cycle is exported to the cytosol and further converted to acetyl-CoA for the synthesis of lipid acids.

Figure 2

The network of Wnt signaling regulates tumor metabolism reprogramming. The activated Wnt signaling pathway promotes the up-regulation of MCT-1, CYC1 and ATP synthase by the downstream transcription factor TCF/LEF, resulting in the secretion of intracellular lactate and the occurrence of aerobic glycolysis. Wnt signaling pathway can also up-regulate the expression of GLUT-1, LDH, PKM2, SLC1A5 and other genes by c-Myc promoting glycolysis, nucleotide and fatty acid synthesis in tumor cells. The non-canonical Wnt signaling pathway promotes aerobic glycolysis by activating Akt-mTOR to stabilize the expression of mTORC1 and β-catenin. The activated mTOR pathway promotes glucose uptake by increasing glucose transporter expression. On the other hand, the mTOR pathway can also lead to an increase in fatty acid synthesis by up-regulating the expression of acetyl-CoA, resulting in an increase in fatty acid oxidative metabolism. In addition, activation of the mTOR pathway can also result in upregulation of glucose-6-phosphate dehydrogenase, resulting in enhanced pentose phosphate bypass and promotion of ribonucleic acid synthesis. ROS levels can directly affect the transcriptional activity of β-catenin. ROS can interact with TCF4, alter the binding of β-catenin to TCF, and interact with the transcriptional link factor of FOXO3a, thereby changing the gene expression of cells and promoting tumorigenesis.