The roles of glycolysis in osteosarcoma

Abstract

Metabolic reprogramming is of great significance in the progression of various cancers and is critical for cancer progression, diagnosis, and treatment. Cellular metabolic pathways mainly include glycolysis, fat metabolism, glutamine decomposition, and oxidative phosphorylation. In cancer cells, reprogramming metabolic pathways is used to meet the massive energy requirement for tumorigenesis and development. Metabolisms are also altered in malignant osteosarcoma (OS) cells. Among reprogrammed metabolisms, alterations in aerobic glycolysis are key to the massive biosynthesis and energy demands of OS cells to sustain their growth and metastasis. Numerous studies have demonstrated that compared to normal cells, glycolysis in OS cells under aerobic conditions is substantially enhanced to promote malignant behaviors such as proliferation, invasion, metastasis, and drug resistance of OS. Glycolysis in OS is closely related to various oncogenes and tumor suppressor genes, and numerous signaling pathways have been reported to be involved in the regulation of glycolysis. In recent years, a vast number of inhibitors and natural products have been discovered to inhibit OS progression by targeting glycolysis-related proteins. These potential inhibitors and natural products may be ideal candidates for the treatment of osteosarcoma following hundreds of preclinical and clinical trials. In this article, we explore key pathways, glycolysis enzymes, non-coding RNAs, inhibitors, and natural products regulating aerobic glycolysis in OS cells to gain a deeper understanding of the relationship between glycolysis and the progression of OS and discover novel therapeutic approaches targeting glycolytic metabolism in OS.

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model

“…The FDG-PET imaging reveals that both ZR2002 and JS84 were able to statistically reduce the total glycolytic activity (TLG parameter, Figure 3 C), and we speculate that the inhibition of the EGFR signaling pathway may have interfered indirectly with the reduction in the glycolytic pathway, decelerating the tumor proliferation. In fact, it has been previously observed that EGF signaling activates the first step in glycolysis with hexokinase 2 (HK2) but impedes the last step with pyruvate kinase muscle isozyme M2 (PKM2) in triple breast cancer cells [ 37 ], and that PKM2 expression is aberrantly high in osteosarcoma tissues [ 38 ]. A direct link between PKM2 expression and EGFR activity was also established in human glioblastoma specimens [ 39 ].…”

Metabolic reprogramming in osteosarcoma

“…found that serine‐threonine kinase receptor‐associated protein was up‐regulated during OS progression, enhancing the metastatic ability of OS cells 74 . Some studies have found that inhibition of serine/threonine protein kinases: glycogen synthase kinase‐3β (GSK‐3β), cyclin G‐associated kinase, Polo‐like kinase 1, glycogen synthase kinase 3β (GSK3β), and Polo‐like kinase 2 reduce the malignant phenotype of OS 9,75–79 . Other studies have found that inhibition of serine/threonine protein phosphatases: serine/threonine protein phosphatase 2A (PP2A) and serine/threonine phosphatase type 5 reduce the viability of OS cells 80–82 …”

“…Glutamine metabolism drives cancer growth and progression for DNA damage repair, epigenetic modification and immune regulation 8 . Glutamine fuels the tricarboxylic acid (TCA) cycle and acts as a redox donor during the Warburg effect 9 . Increased fatty acid synthesis in cancer cells facilitates membrane biosynthesis and signaling molecules.…”

“…8 Glutamine fuels the tricarboxylic acid (TCA) cycle and acts as a redox donor during the Warburg effect. 9 Increased fatty acid synthesis in cancer cells facilitates membrane biosynthesis and signaling molecules. Glucose metabolism, amino acid metabolism and lipid metabolism intersect in the TCA cycle.…”

Identification of four metabolic subtypes and key prognostic markers in lung adenocarcinoma based on glycolytic and glutaminolytic pathways

“…Cellular metabolic pathways mainly include glycolysis, lipid metabolism, glutaminolysis and oxidative phosphorylation [ 5 ]. The metabolism of cancer cells differs from that of normal cells in that they have elevated levels of metabolism and maintain a high proliferation rate that is used to resist some cell death signals [ 6 ].…”