Inhibition of LDHB suppresses the metastatic potential of lung cancer by reducing mitochondrial GSH catabolism

Abstract

Metastasis, the leading cause of cancer death, is closely linked to lactate metabolism. Our study aimed to investigate the role of lactate dehydrogenase B (LDHB), which mainly catalyzes the conversion of lactate to pyruvate, in the metastatic potential of lung cancer. We found that LDHB silencing reduced the invasion and migration ability of lung cancer cells in vitro. On the molecular level, LDHB silencing decreased the total intracellular levels of the antioxidant glutathione (GSH). Surprisingly, LDHB silencing did not increase cellular or mitochondrial reactive oxygen species (ROS) levels. Furthermore, supplementation with GSH monoethyl ester (GSH-mee), a cell-permeable derivative of GSH, partially restored the reduced in vitro colony formation capacity, the oxygen consumption rate, and the invasion and migration capacity of lung cancer cells after LDHB silencing. Using metabolic inhibitors, we showed that the rescue of colony formation after silencing LDHB by GSH-mee was due to enhanced GSH catabolism by γ-L-Glutamyl transpeptidase (GGT), which was mainly present in the mitochondrial fraction of lung cancer cells. Furthermore, we observed that high GGT expression was a prerequisite for the rescue of migratory capacity by GSH-mee after LDHB silencing. Finally, our in vivo experiments demonstrated that targeting LDHB reduced the metastasis of human and mouse lung cancer cells in immunodeficient and immunocompetent mouse models, respectively. In conclusion, LDHB silencing decreases GSH catabolism mediated by GGT, which is primarily located in the mitochondria of cancer cells. Therefore, targeting LDHB is a promising therapeutic approach for the prevention and treatment of metastatic lung cancer.

Keywords: Glutathione; Lactate dehydrogenase; Lung cancer; Metastasis; Mitochondrial metabolism.