Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Abstract

Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.

The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma

“…This finding bridges the function of Par3 with a relatively well-established field of GBM metabolism, which has been shown to depend on mitochondrial action, glucose oxidation, and glycolysis at least in mice bearing GBM tumors [ 43 ], and in various studies of human GBM [ 44 ]. Furthermore, human GBMs with stem-like characteristics appear to generate their ATP via mitochondrial oxidative phosphorylation in parallel to the generation of ROS [ 45 ].…”

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

“…GSCs preferentially use oxidative phosphorylation, while the rest of the tumor is glycolytic, suggesting a potential role for mitochondrial inhibitor therapy [ 60 ]. As discussed by Van Noorden et al (2021) [ 61 ], GSCs reside in specific hypoxic microenvironments, or niches, where they maintained in a slowly dividing quiescent state, protecting them from the cytotoxic effects of chemotherapy and radiotherapy since these therapeutic strategies only target proliferating cells. It has become generally accepted that proliferating GBMs preferentially use aerobic glycolysis for their ATP production, whereas CSCs preferentially use OXPHOS, although due to low oxygen, anaerobic glycolysis, this would be expected; the advantage of that is these conditions keep the low levels but not excessive levels of ROS, which could be toxic.…”

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

“…Targeting energy metabolism has been suggested as a fruitful therapeutic strategy in GBM [53]. PPARGC1A, the gene encoding PRGC1, a transcriptional coactivator regulating energy metabolism via multiple transcription factor interactions, including the cAMP response element binding (CREB) protein and nuclear respiratory factors (NRFs), is a component of the "mitochondrial biogenesis" pathway.…”