Abstract
Simple SummaryGlioblastoma tumours are the most malignant and common type of central nervous system tumours. Despite aggressive treatment measures, disease recurrence in patients with glioblastoma is inevitable and survival rates remain low. Glioblastoma cells, like other cancer cells, can leverage metabolic pathways to increase their rate of proliferation, maintain self-renewal, and develop treatment resistance. Furthermore, many of the metabolic strategies employed by cancer cells are similar to those employed by stem cells in order to maintain self-renewal and proliferation. One-carbon metabolism and de novo purine synthesis are metabolic pathways that are essential for biosynthesis of macromolecules and have been found to be essential for tumourigenesis. In this review, we summarize the evidence showing the significance of 1-C-mediated de novo purine synthesis in glioblastoma cell proliferation and tumourigenesis, as well as evidence suggesting the effectiveness of targeting this metabolic pathway as a therapeutic modality.Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.
Highlights
Altered cell metabolism is a hallmark of cancer cell biology [1]
Guo et al show that aminoimidazole carboxamide ribonucleotide (AICAR)-mediated AMPK activation leads to negative regulation of glioblastoma cell growth, in EGFR-activated cells [6]. This growth inhibitory effect seems to be mediated through metabolic reprograming, as AICAR treatment resulted in AMPK-mediated inhibition of lipogenesis in EGFR-activated tumours, which could be reversed by exogenous supplementation of malonate and palmitate [6]
Cancer cells and stem cells rely on diverse metabolic strategies to maintain macromolecule synthesis
Summary
Altered cell metabolism is a hallmark of cancer cell biology [1]. Many groups have identified ways in which cancer cells use adaptive metabolic strategies to facilitate the process of tumourigenesis. Metabolic reprogramming in glioma cells has been studied in the context of a variety of mechanisms, including increased Warburg effect and aerobic glycolysis [7,8,9,10], the pentose phosphate pathway (PPP) [11,12,13,14,15], amino acid metabolism [16,17,18,19], oxidative phosphorylation [14,20,21,22,23,24], and lipid metabolism [25,26,27,28,29,30] Many of these metabolic pathways manifest in synthesis of macromolecules needed for proliferation. Further elucidation of the role of 1-C metabolism-related vulnerabilities in glioblastoma might uncover novel mechanisms that mediate and control cell proliferation and reveal effective novel treatment strategies
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