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Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells
Martina Spada1, Cristina Piras2, Vera Piera Leoni1
1Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Abstract:
Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.
Insights
Colorectal cancer cells rely on glutamine. Inhibiting glutaminase with CB-839 affects cancer cell survival and metabolism, offering a potential therapeutic strategy by altering energy pathways.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer cell biology
Background:
- Colorectal cancer (CRC) cells exhibit dependence on glutamine for energy and biosynthesis.
- Glutaminase (GLS) inhibitors, such as CB-839, represent a promising therapeutic strategy for CRC.
- Comprehensive evaluation of CB-839's antitumor effects and metabolic impact in CRC is needed.
Purpose of the Study:
- To assess the impact of CB-839 on CRC cell survival and proliferation.
- To investigate metabolic adaptations, particularly in energy pathways, following CB-839 treatment.
- To explore the role of glutamine metabolism in CRC response to GLS inhibition.
Main Methods:
- Treatment of three CRC cell lines (HCT116, HT29, SW480) with varying CB-839 concentrations.
- Assessment of cytotoxicity (MTT assay), proliferation (flow cytometry), and ATP production (Seahorse XF).
- Metabolomic profiling using GC-MS, 1H-NMR, and targeted analysis of the Krebs cycle.
Main Results:
- HT29 cells demonstrated the highest sensitivity to CB-839.
- CB-839 treatment induced cell cycle alterations and increased glycolytic ATP production in HT29 cells.
- Metabolomic analysis revealed significant changes in the Krebs cycle, glutaminolysis, amino acid, sugar, antioxidant, and organic acid metabolism in treated CRC cells.
Conclusions:
- Glutamine plays a critical role in the metabolic demands of CRC cells.
- CB-839 treatment significantly impacts CRC cell metabolism and survival.
- This study provides a basis for understanding CB-839 response and resistance mechanisms in CRC.
