Reprogramming of glucose metabolism: Metabolic alterations in the progression of osteosarcoma

Abstract

Metabolic reprogramming is an adaptive response of tumour cells under hypoxia and low nutrition conditions. There is increasing evidence that glucose metabolism reprogramming can regulate the growth and metastasis of osteosarcoma (OS). Reprogramming in the progress of OS can bring opportunities for early diagnosis and treatment of OS. Previous research mainly focused on the glycolytic pathway of glucose metabolism, often neglecting the tricarboxylic acid cycle and pentose phosphate pathway. However, the tricarboxylic acid cycle and pentose phosphate pathway of glucose metabolism are also involved in the progression of OS and are closely related to this disease. The research on glucose metabolism in OS has not yet been summarized. In this review, we discuss the abnormal expression of key molecules related to glucose metabolism in OS and summarize the glucose metabolism related signaling pathways involved in the occurrence and development of OS. In addition, we discuss some of the targeted drugs that regulate glucose metabolism pathways, which can lead to effective strategies for targeted treatment of OS.

Keywords: Glucose metabolism; Key enzymes; Osteosarcoma; Signaling pathways; Targeted therapy.

Fig. 1

Non-coding rna and small molecule substances regulate glucose uptake and glycolysis, tricarboxylic acid cycle and pentose phosphate pathway. HK, PFK-1, ALDOA, PGK1, PKM2, LDHA, etc. in glycolysis pathway can participate in OS progression under the regulation of some non-coding RNA and small molecule substances. G-6-PD in the pentose phosphate pathway is involved in the progression of OS under the influence of lncRNAOR3A4. In the tricarboxylic acid cycle pathway, PDC is involved in the progression of OS under the influence of miR-379, miR-15b-5p, and IDH is adjusted by HIF-1 α, SDH is adjusted by TGF-β, these also participate in the progression of OS. GLUT1: glucose transporter 1; HK: hexokinase; G-6-P: Glucose-6-phosphate; F-6-P: Fructose-6-phosphate; PFK-1: Phosphate fructose kinase 1; F-1, 6-BP: fructose-1, 6-diphosphate; ALDLA: aldolase; DHAP: dihydroxyacetone phosphate; PGK1: phosphoglycerate kinase 1; 3PG: triphosphoglycerate; PEP: phosphoenolpyruvic acid; PKM2: pyruvate kinase 2; LDHA: lactate dehydrogenase; LA: Lactic acid; PDC: Pyruvate dehydrogenase complex. The glycolysis pathway and pentose phosphate pathway occur in the cytoplasm, while the tricarboxylic acid cycle occurs in mitochondria.

Fig. 2

Regulation mechanism of signal pathways on the glucose metabolism in the development of OS. There are 5 signaling pathways, mTOR, Wnt, hippo, NF-κB, MAPK, are related to glucose metabolism in OS cells.

Fig. 3

Natural extracts/chemically synthesized substances target the regulation of glucose metabolism pathways in the treatment of OS. caudatin, metformin, CDDO-NFM, pramlintide, resveratrol, glutaminase 1 inhibitor, and apigenin inhibit glycolysis in OS cells; F-AgÅPs promote the tricarboxylic acid cycle in OS cells.

Fig. 4

Regulatory mechanism of OS progression and targeted regulatory mechanism of natural extracts and chemical compounds. 11 key molecules, including GLUT, HK, PFK-1, PGK1, PKM2, ALDOA, LDHA, G-6-PD, PDC, IDH, SDH, participate in OS progression under the regulation of non-coding RNA and small molecular substances. It has been shown that five pathways, including mTOR, Wnt, Hippo, NF-κB and MAPK, are related to the glucose metabolism of OS cells. Among them, natural extracts (apigenin, caudatin, resveratrol) and chemical compounds (2 -(3-cyanopyridine −2-yl) thio) acetamide, F-AgÅPs, CDDO-NFM, metformin, pramlintide, glutaminase 1 inhibitor can affect the progression of OS by targeting glucose metabolism. These molecules and pathways can become potential therapeutic targets for OS.

Fig. 5

Regulation of glucose metabolism by non-coding RNA, related signaling pathways and natural extracts and chemical syntheses in OS. (A) the regulatory mechanisms of non-coding RNA and small molecules on the activities of key enzymes of glucose metabolism in OS; (B) the regulatory mechanisms of natural extracts and chemical compounds on key enzymes of glucose metabolism in OS; (C) the regulatory mechanisms of related signaling pathways on glucose metabolism in OS.