Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

Martins, Filipa; Gonçalves, Luís G.; Pojo, Marta; Serpa, Jacinta

doi:10.3390/biom10101370

Cited by 21 publications

(20 citation statements)

References 215 publications

(292 reference statements)

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“…Thus, considerable and continuous efforts are being directed toward exploiting specific dependencies to identify novel molecular targets and design new effective therapeutic strategies that help improve the patient’s clinical care with GBM ( 8 , 35 , 122 ). Indeed, the paradigm of focusing on cancer metabolism was freshly required beyond the dramatic flexibleness of tumor metabolic cascades reported in cancer cells challenged with multiplex inhibitors, including glycolysis and glutaminase inhibitors ( 123 , 124 ).…”

Section: Targeting Gliomas Metabolism - Current Therapeutic Advances ...mentioning

confidence: 99%

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

et al. 2022

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Glioblastoma multiforme (GBM), a highly invasive and incurable tumor, is the humans’ foremost, commonest, and deadliest brain cancer. As in other cancers, distinct combinations of genetic alterations (GA) in GBM induce a diversity of metabolic phenotypes resulting in enhanced malignancy and altered sensitivity to current therapies. Furthermore, GA as a hallmark of cancer, dysregulated cell metabolism in GBM has been recently linked to the acquired GA. Indeed, Numerous point mutations and copy number variations have been shown to drive glioma cells’ metabolic state, affecting tumor growth and patient outcomes. Among the most common, IDH mutations, EGFR amplification, mutation, PTEN loss, and MGMT promoter mutation have emerged as key patterns associated with upregulated glycolysis and OXPHOS glutamine addiction and altered lipid metabolism in GBM. Therefore, current Advances in cancer genetic and metabolic profiling have yielded mechanistic insights into the metabolism rewiring of GBM and provided potential avenues for improved therapeutic modalities. Accordingly, actionable metabolic dependencies are currently used to design new treatments for patients with glioblastoma. Herein, we capture the current knowledge of genetic alterations in GBM, provide a detailed understanding of the alterations in metabolic pathways, and discuss their relevance in GBM therapy.

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Section: Targeting Gliomas Metabolism - Current Therapeutic Advances ...mentioning

confidence: 99%

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

et al. 2022

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“…Cells having different metabolic phenotypes, with or without TRAP1, were forced to rely on either glucose, pyruvate, or glutamine as the sole carbon source. Surprisingly, consistent among all the cell types considered, TRAP1-deficient cells were unable to support OxPhos with either glucose or pyruvate, instead relying on glutamine, which served as an anaplerotic molecule [ 95 ] to support the TCA cycle and OxPhos upon conversion to α-ketoglutarate in mitochondria. Confusingly, all these metabolic behaviors are pro-neoplastic [ 85 , 96 , 97 , 98 ].…”

Section: Cancer and Metabolic Rewiringmentioning

confidence: 99%

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

et al. 2022

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The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis.

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“…A continuous supply of precursors, sustained by anaplerotic pathways, “refills” the cycle with intermediates to replace those that have been already used for biosynthesis. Glutaminolysis, which produces α-ketoglutarate from glutamine, and pyruvate carboxylation, which produces oxaloacetate from glucose/pyruvate are major contributors to anaplerotic fluxes in cancer cells ( Bott et al, 2019 ; Martins et al, 2020 ; Kiesel et al, 2021 ). Oxidation of the branched-chain amino acids (BCAAs) isoleucine and valine also provides an anaplerotic flux in some tumors.…”

Section: Vdac Opening Mitochondrial Metabolism and Warburg Effectmentioning

confidence: 99%

VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

2021

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Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.

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Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

Cited by 21 publications

References 215 publications

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

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