The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia

Sho Tabata ¹, Hiroko Endo ², Hideki Makinoshima ³

⁰Institute for Advanced Biosciences, Keio University, Tsuruoka, Tsuruoka, 997-0052, Japan; Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, 997-0052, Japan; Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan.

Biochemical and Biophysical Research Communications +

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April 25, 2024

View abstract on PubMed

Summary

Chronic hypoxia in colorectal cancer (CRC) alters metabolism, activating the gamma-glutamyl cycle for amino acid supply. Inhibiting this cycle reverses metabolic changes, offering new insights into cancer metabolism.

Area Of Science

Oncology
Cancer Metabolism
Biochemistry

Background

Malignant tumors often exhibit a hypoxic microenvironment, necessitating metabolic reprogramming for survival.
Metabolic adaptations are crucial for energy production and oxidative stress resistance in cancer cells.
Limited research exists on metabolic changes induced by chronic hypoxia compared to acute hypoxia.

Purpose Of The Study

To comprehensively analyze metabolic changes in colorectal cancer (CRC) under chronic hypoxia.
To identify metabolic pathways involved in CRC adaptation to chronic hypoxia.
To investigate the role of the gamma-glutamyl cycle in CRC under chronic hypoxic conditions.

Main Methods

Utilized a chronic hypoxia model with colorectal cancer (CRC) organoids.
Performed comprehensive metabolic analysis to track changes over time.
Investigated the gamma-glutamyl cycle by inhibiting key enzymes (GGCT and GGT1) via knockdown.

Main Results

Chronic hypoxia led to increased 5-oxoproline and decreased oxidized glutathione (GSSG) compared to acute hypoxia.
Inhibition of the gamma-glutamyl cycle reversed the upregulation of 5-oxoproline and several amino acids.
Knockdown of gamma-glutamyl transferase 1 (GGT1) reduced intracellular gamma-glutamyl amino acid levels.

Conclusions

The gamma-glutamyl cycle functions as a critical amino acid supply system in colorectal cancer under chronic hypoxia.
These findings provide novel insights into cancer metabolism and potential therapeutic targets in chronic hypoxic environments.
Targeting the gamma-glutamyl cycle may represent a strategy to disrupt cancer cell adaptation to chronic hypoxia.

Keywords:

Amino acid metabolism CTOS Colorectal cancer Organoid γ-glutamyl amino acids γ-glutamyl cycle

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