D-2-Hydroxyglutarate in Glioma Biology

Chou, Fu-Ju; Liu, Yang; Lang, Fengchao; Yang, Chunzhang

doi:10.3390/cells10092345

Cited by 45 publications

(22 citation statements)

References 156 publications

(185 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, WNT inhibition of glucose-deprived GSCs affected several oncometabolites, such as hydroxyglutarate, myo-inositol, succinate, and fumarate. Hydroxyglutarate is an oncometabolite that accumulates in IDH-mutant glioma cells and correlates with poor prognosis [35]. In our study, hydroxyglutarate was significantly reduced under LGK974 treatment, suggesting a role of the WNT pathway in regulating oncometabolic-driven cancer growth.…”

Section: Discussionsupporting

confidence: 48%

WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells

Yusuf

Aretz

Nickel

et al. 2022

Cancers

View full text Add to dashboard Cite

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions.

show abstract

Section: Discussionsupporting

confidence: 48%

WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells

Yusuf

Aretz

Nickel

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Multiple trials of various mutant IDH inhibitors for glioma are currently underway [ 41 , 42 ] following the promising results of a phase 1 trial [ 43 ]. Although these drugs are effective in reducing D -2-hydroxyglutarate levels and inducing cell differentiation, and some are brain penetrant, the clinical outcomes still remain to be seen for the following reasons [ 41 , 42 , 44 , 45 , 46 ]. First, both IDH mutation and D -2-hydroxyglutarate are seemingly nonessential in glioma progression.…”

Section: Targeting Idh-mutant Gliomamentioning

confidence: 99%

Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

Huang

2022

Biomedicines

View full text Add to dashboard Cite

Although hotspot mutations in isocitrate dehydrogenase (IDH) genes are associated with favorable clinical outcomes in glioma, CDKN2A/B homozygous deletion has been identified as an independent predicator of poor prognosis. Accordingly, the 2021 edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has adopted this molecular feature by upgrading IDH-mutant astrocytoma to CNS WHO grade IV, even in the absence of glioblastoma-specific histological features—necrosis and microvascular proliferation. This new entity of IDH-mutant astrocytoma not only signifies an exception to the generally favorable outcome of IDH-mutant glioma, but also brings into question whether, and, if so, how, CDKN2A/B homozygous deletion overrides the anti-tumor activity of IDH mutation by promoting the proliferation of stem/neural progenitor-like cells. Understanding the mechanism by which IDH mutation requires intact tumor-suppressor genes for conferring favorable outcome may improve therapeutics.

show abstract

“…2-KG is an indispensable cofactor for 2-KG-dependent dioxygenases (2-KDDs). The mutated IDHs could convert isocitrate to 2-KG and then reduce 2-KG to α-hydorxyglutarate (2-HG) using NADPH [ 88 , 89 ]. Owing to their similar chemical structures [ 90 , 91 ], 2-KG and 2-HG could competitively bind to 2-KDDs.…”

Section: Idh Mutations and Aa Metabolic Alterationmentioning

confidence: 99%

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

et al. 2022

View full text Add to dashboard Cite

Amino acids (AAs) are indispensable building blocks of diverse bio-macromolecules as well as functional regulators for various metabolic processes. The fact that cancer cells live with a voracious appetite for specific AAs has been widely recognized. Glioma is one of the most lethal malignancies occurring in the central nervous system. The reprogrammed metabolism of AAs benefits glioma proliferation, signal transduction, epigenetic modification, and stress tolerance. Metabolic alteration of specific AAs also contributes to glioma immune escape and chemoresistance. For clinical consideration, fluctuations in the concentrations of AAs observed in specific body fluids provides opportunities to develop new diagnosis and prognosis markers. This review aimed at providing an extra dimension to understanding glioma pathology with respect to the rewired AA metabolism. A deep insight into the relevant fields will help to pave a new way for new therapeutic target identification and valuable biomarker development.

show abstract

D-2-Hydroxyglutarate in Glioma Biology

Cited by 45 publications

References 156 publications

WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells

WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells

Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

Contact Info

Product

Resources

About