Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach

Abstract

Brain cancers demonstrate a complex metabolic behavior so as to adapt the external hypoxic environment and internal stress generated by reactive oxygen species. To survive in these stringent conditions, glioblastoma cells develop an antagonistic metabolic phenotype as compared to their predecessors, the astrocytes, thereby quenching the resources expected for nourishing the neurons. The complexity and cumulative effect of the large scale metabolic functioning of glioblastoma is mostly unexplored. In this study, we reconstruct a metabolic network comprising of pathways that are known to be deregulated in glioblastoma cells as compared to the astrocytes. The network, consisted of 147 genes encoding for enzymes performing 247 reactions distributed across five distinct model compartments, was then studied using constrained-based modeling approach by recreating the scenarios for astrocytes and glioblastoma, and validated with available experimental evidences. From our analysis, we predict that glycine requirement of the astrocytes are mostly fulfilled by the internal glycine-serine metabolism, whereas glioblastoma cells demand an external uptake of glycine to utilize it for glutathione production. Also, cystine and glucose were identified to be the major contributors to glioblastoma growth. We also proposed an extensive set of single and double lethal reaction knockouts, which were further perturbed to ascertain their role as probable chemotherapeutic targets. These simulation results suggested that, apart from targeting the reactions of central carbon metabolism, knockout of reactions belonging to the glycine-serine metabolism effectively reduce glioblastoma growth. The combinatorial targeting of glycine transporter with any other reaction belonging to glycine-serine metabolism proved lethal to glioblastoma growth.

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

“…Moreover, astrocytes activated 52% of model reactions (Figure 3) and preferentially use a glucose-based metabolism. Our model also shows that glucose is catabolized and constitutively released by astrocytes as lactate without any Pathways Involved in Palmitic Acid Toxicity stimuli similar (Le Foll and Levin, 2016), in agreement with Cakir et al (2007) and Bhowmick et al (2015) whom reported a lactate release rate of 8.9% from the glucose flux in resting conditions (Çakir et al, 2007;Bhowmick et al, 2015). As previously stated, astrocytes in physiological conditions release large amounts of lactate to the extracellular space (Mangia et al, 2009), which can be used by neurons to supply their energetic requirements (Kumar Jha et al, 2016).…”

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

“…While carbon metabolism KEGG pathway was identified for deiminated proteins in both GBM cell lines, KEGG pathway for central carbon metabolism in cancer was identified in LN18 cells only. Carbon metabolism is related to metabolic adaption and growth in GBM [125,126], including in TMZ resistance [127] and in the control of glioma cell transformation to a higher aggressive stage [109]. Roles for post-translational deimination in such metabolic control have not been investigated and may be of relevance as this pathway was prominent for deimination in LN18 cells, which present a more aggressive and chemo-resistant form than LN229 [69].…”

Reconstructed Metabolic Network Models Predict Flux-Level Metabolic Reprogramming in Glioblastoma

“…Although there are several studies to apply genome-scale constraint-based modeling to cancer metabolism, an analysis of brain tumors with this approach is scarce. Only a recent study analyzed GBM with the FBA approach, by using a metabolic model with 147 genes and 12 pathways, without the incorporation of gene expression data (Bhowmick et al, 2015 ). Our work provides a much more comprehensive coverage of brain tumor metabolism.…”