Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export

作者：Hoon Choi, Mamta Gupta, Arjun Sengupta, Emma E. Furth, Christopher Hensley, Aalim M. Weljie, Hsiaoju Lee, Yuting Lu, Austin Pantel, David A. Mankoff, Rong Zhou · 发表于：Neoplasia · 年份：2025 · DOI：10.1016/j.neo.2025.101136 · 被引用次数：13 · 研究领域：Cancer, Hypoxia, and Metabolism、Metabolomics and Mass Spectrometry Studies、Cancer, Lipids, and Metabolism

• TNBC cells exhibit high glutaminase activity and maintain a large cellular glutamate pool. • Blockade of glutaminase and glutamate/cystine antiporter induced oxidative stress. • Dual blockade plus doxorubicin depleted cellular glutathione and induced apoptosis. • Dual blockade enhanced cisplatin efficacy to overcome chemoresistant TNBC tumor. • Changes of metabolites induced by metabolic blockade precede changes in mRNA. Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo . Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis th...