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Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in
Kenji Miki1,2, Mikako Yagi3, Ryusuke Hatae1
1Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Higashi-Ku, Fukuoka, 812-8582, Japan.
Background:
Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
Methods:
We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
Results:
The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
Conclusions:
Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.
Insights
Glioblastoma exhibits two metabolic types: glycolytic-dominant and mitochondrial-dominant. Inhibiting glutaminolysis effectively suppressed tumor growth in the mitochondrial-dominant type, suggesting a targeted therapeutic strategy for glioblastoma.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glioblastoma, an aggressive brain cancer, necessitates metabolic reprogramming for tumor growth.
- While metabolic pathway activation is known in glioblastoma cell lines, a comprehensive profile in patient tissues is lacking.
- Understanding these metabolic shifts is crucial for developing effective glioblastoma treatments.
Purpose of the Study:
- To comprehensively profile metabolic reprogramming in glioblastoma tissues.
- To elucidate the role of specific metabolic pathways, including glycolysis and glutaminolysis, in glioblastoma.
- To investigate the potential of targeting metabolic pathways for glioblastoma therapy.
Main Methods:
- Analysis of 38 glioblastoma tissues (20 test set, 18 validation set) from Kyushu and Kagoshima University Hospitals.
- Focus on proteins involved in glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle.
- Validation using six glioblastoma cell lines, including patient-derived cells.
Main Results:
- Mitochondria-related proteins (COX1, COX2, DRP1) correlated with glutaminolysis proteins (GLDH, GLS1).
- Expression of mitochondrial and glutaminolysis proteins was inversely correlated with glycolytic proteins.
- Inhibition of glutaminolysis effectively suppressed tumor growth in cell lines with high GLDH/GLS1 expression.
Conclusions:
- Glioblastoma tissues can be classified into glycolytic-dominant and mitochondrial-dominant types.
- The mitochondrial-dominant type is characterized by glutaminolysis dominance.
- Targeting the glutaminolysis pathway presents a potential therapeutic strategy for mitochondrial-dominant glioblastoma.
