The Relationship Between Metabolic Reprogramming and Glutamine Metabolism in Glioblastoma

Background Introduction

Glioblastoma is a highly aggressive primary brain tumor with a very poor prognosis. Although current standard treatments include surgery, radiotherapy, and chemotherapy, there is no cure for the disease. In recent years, metabolic reprogramming has been recognized as one of the key mechanisms by which cancer cells sustain rapid proliferation. Glioblastoma cells adapt to the nutrient-limited tumor microenvironment by altering metabolic pathways such as glycolysis, mitochondrial oxidative phosphorylation, and glutaminolysis. However, the specific roles and interrelationships of these metabolic pathways in glioblastoma tissues remain unclear.

This study aims to reveal the relationship between mitochondrial-related proteins and glutamine metabolism by analyzing tumor tissue samples from glioblastoma patients and to explore the role of these metabolic pathways in tumor growth. The research team hopes that these findings will provide new metabolic targets for glioblastoma treatment.

Source of the Paper

The study was conducted by a research team from Kyushu University and Kagoshima University in Japan. The main authors include Kenji Miki, Mikako Yagi, Ryusuke Hatae, and others, with Koji Yoshimoto as the corresponding author. The results were published in 2024 in the journal Cancer & Metabolism, under the title Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Research Process and Results

1. Research Samples and Experimental Design

The research team first analyzed 20 glioblastoma tissue samples from Kyushu University Hospital as a test set, followed by 18 samples from Kagoshima University Hospital as a validation set. Additionally, the study used six glioblastoma cell lines (including U87, LN229, U373, and T98G) and two patient-derived cell lines (KNS1435 and KNS1451) for in vitro validation.

2. Expression Analysis of Metabolic Pathway-Related Proteins

Using Western blotting, the team detected the expression levels of proteins related to various metabolic pathways in tumor tissues, including HK2 for glycolysis, SHMT2 and MTHFD1 for one-carbon metabolism, GLS1 and GLDH for glutaminolysis, and COX1, COX2, and DRP1 for mitochondrial-related proteins. The results showed that the expression levels of mitochondrial-related proteins (COX1, COX2, and DRP1) were correlated with each other and positively correlated with glutaminolysis-related proteins (GLS1 and GLDH). Conversely, the expression of mitochondrial-related proteins was inversely correlated with glycolysis-related proteins such as HK2.

3. Relationship Between Mitochondria and Glutamine Metabolism

The study further revealed that the expression of mitochondrial-related proteins was closely associated with glutamine metabolism. Specifically, under glucose-starved conditions, the expression of both mitochondrial-related proteins and glutaminolysis-related proteins was significantly upregulated. This suggests that mitochondria-dominant tumor cells rely on glutamine metabolism to maintain energy supply.

4. Therapeutic Effects of Glutaminolysis Inhibitors

To validate the therapeutic potential of glutamine metabolism in glioblastoma, the research team treated cell lines with high expression of GLDH and GLS1 (such as LN229, U373, and T98G) with GLDH inhibitor (R162) and GLS1 inhibitor (BPTES). The results showed that these inhibitors significantly suppressed tumor cell growth, indicating that glutaminolysis inhibitors may have therapeutic potential for mitochondria-dominant glioblastoma.

5. Metabolomics Analysis

The research team also conducted metabolomics analysis on tumor tissues using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that citric acid levels were significantly reduced in mitochondria-dominant tumor tissues, indicating that these tissues rely on the tricarboxylic acid (TCA) cycle for energy metabolism.

Conclusions and Significance

This study revealed the close relationship between mitochondrial-related proteins and glutamine metabolism in glioblastoma tissues and confirmed that glioblastoma can be categorized into glycolysis-dominant and mitochondria-dominant types. Mitochondria-dominant tumor cells rely on glutamine metabolism, making the inhibition of glutaminolysis a potential effective strategy for treating this type of tumor.

Research Highlights

1. Revealing Metabolic Heterogeneity: The study is the first to identify the existence of glycolysis-dominant and mitochondria-dominant metabolic types in glioblastoma tissues and to reveal their relationship with glutamine metabolism.
2. Discovery of Therapeutic Targets: The study confirmed the potential of glutaminolysis inhibitors in suppressing the growth of mitochondria-dominant glioblastoma, providing experimental evidence for the development of new treatment strategies.
3. Integration of Metabolomics and Proteomics: Through the combined analysis of metabolomics and proteomics, the research team provided an in-depth understanding of the complexity of tumor metabolism, offering new methodological references for future metabolic research.

Future Prospects

Although this study provides important insights into metabolic therapy for glioblastoma, some questions remain to be explored. For example, the spatiotemporal heterogeneity of tumor metabolism, dynamic changes in metabolic pathways, and the clinical efficacy of glutaminolysis inhibitors. Future research could use spatial transcriptomics and metabolomics technologies to further reveal the complexity of tumor metabolism and provide more precise metabolic targets for personalized treatment.

This study not only deepens our understanding of metabolic reprogramming in glioblastoma but also provides important experimental evidence for the development of metabolism-based treatment strategies.