A new insight into Glutamine promoting tumor proliferation: The mitochondrial metabolic pathway - Gln/GGCT/GSH/ROS axis

γ-Glutamylcyclotransferase (GGCT) is a crucial enzyme for glutathione (GSH) metabolism. Little is known about its role in the process of glutamine (Gln) affecting tumor progression. The research found that Gln was significantly increased and promoted tumor growth. It promoted the proliferation of hepatocellular carcinoma and prostate cancer cells by reducing the production of reactive oxygen species (ROS) and increasing GSH levels. GGCT was correlated with Gln concentration. The depletion of GGCT inhibited cell proliferation, decreased GSH levels and promoted ROS production, while overexpression had the opposite effects. miR-29b-3p mediated the decrease in GGCT expression under Gln-deficient conditions. GGCT affected mitochondrial morphology and regulated oxidative phosphorylation. It also affected tricarboxylic acid (TCA) cycle metabolism.. GGCT knockdown significantly inhibited tumor growth and promoted ROS production, whereas N-acetylcysteine increased tumor growth and reduced ROS production in vivo. In conclusion, GGCT maintains mitochondrial metabolism through the Gln-GGCT-GSH-ROS axis, providing a promising therapeutic approach for cancer treatment.