Metabolic Reprogramming in Glioma

Abstract

Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

A Novel Tumor-Suppressor, CDH18, Inhibits Glioma Cell Invasiveness Via UQCRC2 and Correlates with the Prognosis of Glioma Patients

“…Third, the ketogenic diet is a high-fat and low-carbohydrate diet that used in treating gliomas for years [40]. Our results explain to some extent why a ketogenic diet could be an optional therapy for gliomas because unlike normal brain cells, the tumor cells have relatively low expression of CDH18 and UQCRC2, which contributes to the lack of a functional OXPHOS system necessary for metabolism of ketones for energy production [37,39]. However, this hypothesis for ketogenic diet in gliomas needs further investigation.…”

“…Since CDH18 is firstly studied in gliomas, whether its expression and functions are altered between different molecular subgroups of gliomas remains unexplored. Second, it was revealed that the levels of OXPHOS are down-regulated in glioma cells due to several reasons, one of which is the direct loss of function of components of OXPHOS, such as complex II, III and IV [38,39]. Since UQCRC2 is a core component of complex III, we infer that the down-regulation of CDH18 in gliomas inhibits the expression of UQCRC2 protein, which contributes to the loss of function of complex III and decreased activity of OXPHOS in gliomas.…”

miR‐128‐3p contributes to mitochondrial dysfunction and induces apoptosis in glioma cells via targeting pyruvate dehydrogenase kinase 1

“…Furthermore, as glioma proliferate, they expand beyond existing blood supply, intensifying the hypoxic environment. Numerous studies point to a molecular escape mechanism that exchanges energy production from aerobic mitochondrial OXPHOS to anaerobic cytoplasmic glycolysis in glioma . Though OXPHOS metabolism provides more ATPs than that in glycolytic metabolism, glycolysis could provide proliferative and survival advantages through decreasing the reliance on aerobic respiration in glioma .…”

Amino acid metabolism‐related gene expression‐based risk signature can better predict overall survival for glioma

“…In our study, we focused on gliomas, the most common form of primary malignant brain tumor, which can be subdivided into grades II‐IV in light of WHO classification. Compared with WHO Grades II‐III, which comprise LGG, GBM WHO IV bears a dismal prognosis with median survival rates of 14.6 months . The 2016 WHO classification of central nervous system (CNS) tumors combines molecular parameters and histology to define diffuse gliomas .…”

“…Compared with WHO Grades II-III, which comprise LGG, GBM WHO IV bears a dismal prognosis with median survival rates of 14.6 months. [14][15][16] The 2016 WHO classification of central nervous system (CNS) tumors combines molecular parameters and histology to define diffuse gliomas. 17 Based on traditional histopathology but enriched with IDH and 1p/19q codeletion status, gliomas could be classified into five subtypes (three LGG and two GBM), as follows: (i) LGG with wild-type IDH (LGG-IDHwt); (ii) LGG with IDH mutation and 1p/19q non-codeletion (LGG-IDHmut-noncodel); (iii) LGG with IDH mutation and 1p/19q codeletion (LGG-IDHmut-codel); (iv) GBM with wild-type IDH (GBM-IDHwt); and (v) GBM with IDH mutation (GBM-IDHmut).…”