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Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation

2010; Cell Press; Volume: 18; Issue: 3 Linguagem: Inglês

10.1016/j.ccr.2010.08.009

1878-3686

Jianbin Wang, Jon W. Erickson, Reina N. Fuji, Sekar Ramachandran, Ping Gao, Ramani Dinavahi, Kristin F. Wilson, A.L.B. Ambrosio, Sandra Martha Gomes Dias, Chi V. Dang, Richard A. Cerione,

Amino Acid Enzymes and Metabolism

Summary Rho GTPases impact a number of activities important for oncogenesis. We describe a small molecule inhibitor that blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NF-κB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.