The regulatory roles and clinical significance of glycolysis in tumor

Abstract

Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.

Keywords: biomarkers; glycolysis; targeted therapy; tumor development.

FIGURE 1

The regulatory role of glycolysis in tumor development. Glycolytic enzymes and products affect the biological behavior of tumor cells, including cell proliferation, cell cycle regulation, EMT, metastasis, autophagy, and angiogenesis. Abbreviations: 1,3‐BPG, 1,3‐bisphosphoglycerate; 2‐PGA, 2‐phosphoglycerate; 3‐PGA, 3‐phosphoglycerate; ALDO, aldolase; DHAP, dihydroxyacetone phosphate; ENO, enolase; F‐1,6‐BP, fructose‐1,6‐bisphosphate; F‐6‐P, fructose‐6‐phosphate; G‐3‐P, glyceraldehyde‐3‐phosphate; G‐6‐P, glucose‐6‐phosphate; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; HK, hexokinase; LDH, lactate dehydrogenase; PEP, phosphoenolpyruvate; PFK‐1 phosphofructokinase‐1; PGAM, phosphoglycerate mutase; PGI, phosphohexose isomerase; PGK, phosphoglycerate kinase; PK, pyruvate kinase.

FIGURE 2

The effects of glycolysis on TME. The enhanced glycolytic process in tumor cells promotes the production of excess lactate into TME. Lactate inhibits the tumor‐killing ability of NK cells and T cells through MAPKs p38 and JNK/c‐Jun signaling pathways, which promotes the immune escape of tumor cells. Moreover, Lactate can reduce the secretion of IL‐6 and TNF‐α of DC, which inhibits the killing effect of immune cells on tumor cells. LDHA, the key product of glycolysis, induces the conversion of M1 TAMs to M2 TAMs, which promotes tumor proliferation, invasion and metastasis. Abbreviations: DC, dendritic cell; IL‐6, interleukin 6; NK, nature killer; TAM, tumor‐associated macrophage; TME, tumor microenvironment; TNF‐α, tumor necrosis factor‐alpha.

FIGURE 3

The application of glycolysis in the diagnosis and treatment of tumors. 2‐DG can be taken orally and ATO can be administered intravenously for the treatment of patients with tumors, Wherein the ATO can be used to treat tumors by administration alone or in combination with other drugs. Glycolytic enzymes such as HK2, PKM2 are upregulated in the serum of tumor patients before treatment, indicating that they can serve as promising diagnostic biomarkers. Intracranial tumors show different degrees of glycolysis, different sizes of various elemental peaks, different MRS signals, indicating different degrees of malignancy. PET/CT shows increased 2‐[¹⁸F] FDG uptake due to enhanced glycolysis in lung cancer tissues. Drugs such as shikonin, C3K, and PB2 prevent PKM2 elevation in tumor tissues, and similarly, drugs including 2‐DG, ATO, and Gen‐27 block HK2 expression in tumor tissues. Abbreviations: 2‐DG, 2‐Deoxy‐D‐glucose; 2‐[¹⁸F] FDG, 2‐[¹⁸F] fluoro‐2‐deoxy‐d‐glucose; ATO, Arsenic Trioxide; ENO, enolase; HK, hexokinase; LDH, lactate dehydrogenase; MRS, magnetic resonance spectrum; PB2, proanthocyanidin B2; PET/CT, positron emission tomography/computed tomography; PK, pyruvate kinase.