Abstract
Background: Epithelial-mesenchymal transition (EMT) in cancer cell metastasis involves complicated metabolic plasticity to survive the highly challenging environment, such as oxidative stress, after subsequent circulation in the bloodstream. Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine (Gln) during Gln deprivation stress. This study revealed for the first time that GS plays an important role in protecting triple-negative breast cancer (TNBC) cells from ferroptosis during Gln deprivation-induced EMT, namely ferroptosis-resistant EMT (FR-EMT). Methods: To better understand this finding, we focused on the mechanism of GS-mediated FR-EMT in TNBC through transcriptomic analysis and murine metastasis modeling. Results: This study specifically investigated the effects of GS on lipid peroxidation and iron metabolism, the two major metabolic disorders in ferroptosis. An abnormal increase in monounsaturated fatty acids (MUFAs) mediated by mechanistic target of rapamycin complex 1 (mTORC1) decreased the ferroptosis sensitivity under Gln deprivation. Additionally, aberrant iron metabolism via lipocalin 2 (LCN2) and transferrin receptor (TFRC) affected the sensitivity to ferroptosis. Moreover, this study confirmed that GS protects TNBC cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood in the lung metastasis mouse model. Conclusion: This investigation provides insights into the role of ferroptosis in metastasis and demonstrates that GS may be a viable target for preventing metastases in TNBC.