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Published on: May 9, 2025
D-2HG Inhibits Glutamine Synthetase Activity and Induces Senescence in IDH-Mutant Gliomas
Yuanlin Zhao1, Jiankuan Shi2, Yuan Yuan1
1State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Abstract:
IDH1/2 mutations are prevalent genetic alterations in gliomas that facilitate metabolic reprogramming and epigenetic modifications, which are essential for glioma progression. However, their exact contributions to tumorigenesis remain to be fully elucidated. Cellular senescence is a known precursor to tumorigenesis, and multiple oncogenes can initiate this senescence program. Our study demonstrated that the IDH1 mutation inhibits the proliferation of astrocytes and glioma cells, inducing cellular senescence through mechanisms involving DNA damage and increased production of reactive oxygen species (ROS). Notably, these effects were mitigated by the addition of exogenous glutamine. Within cells, glutamine synthetase (GS) serves as the sole enzyme responsible for glutamine synthesis. We found that D-2-hydroxyglutarate (D-2HG), an oncometabolite generated by mutant IDH enzymes, directly inhibits GS activity by binding to the glutamate site, substantially reducing endogenous glutamine production and exacerbating senescence in IDH1-mutant glioma cells. Additionally, in human glioma samples, a greater prevalence of GS-positive astrocytes was detected in IDH-mutant gliomas, likely providing adequate glutamine to sustain growth and mitigate senescence in these cells. Our findings suggest that D-2HG promotes senescence in IDH1-mutant glioma cells by inhibiting GS activity and that disrupting glutamine transport between astrocytes and glioma cells may constitute a promising therapeutic strategy for targeting IDH-mutant gliomas.
Insights
IDH1 mutations induce cellular senescence in glioma cells by inhibiting glutamine synthesis. Targeting glutamine transport may offer a new therapeutic strategy for IDH-mutant gliomas.
Area of Science:
- Oncology
- Metabolic pathways
- Cellular senescence
Background:
- Isocitrate dehydrogenase (IDH) mutations are common in gliomas, driving metabolic reprogramming crucial for tumor growth.
- Cellular senescence, a state of irreversible cell cycle arrest, can be a precursor to tumorigenesis.
- The precise role of IDH mutations in initiating senescence and their impact on glioma progression require further investigation.
Purpose of the Study:
- To investigate the role of IDH1 mutations in inducing cellular senescence in glioma cells.
- To elucidate the underlying mechanisms, including the involvement of reactive oxygen species (ROS) and glutamine metabolism.
- To explore potential therapeutic strategies targeting glutamine metabolism in IDH-mutant gliomas.
Main Methods:
- Assessing the effect of IDH1 mutation on astrocyte and glioma cell proliferation and senescence.
- Measuring DNA damage and ROS production.
- Investigating the inhibitory effect of D-2-hydroxyglutarate (D-2HG) on glutamine synthetase (GS) activity.
- Analyzing GS expression in human glioma samples.
Main Results:
- IDH1 mutation was found to inhibit proliferation and induce senescence in glioma cells via DNA damage and increased ROS.
- Exogenous glutamine addition mitigated these senescence-inducing effects.
- The oncometabolite D-2HG directly inhibited GS activity, reducing endogenous glutamine production and worsening senescence.
- Increased GS-positive astrocytes were observed in IDH-mutant gliomas, suggesting a role in providing glutamine.
Conclusions:
- D-2HG promotes senescence in IDH1-mutant glioma cells by inhibiting GS activity and reducing glutamine synthesis.
- Disrupting glutamine transport between astrocytes and glioma cells presents a potential therapeutic avenue for IDH-mutant gliomas.
