Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation

SummaryRho 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.

► Rho GTPase signaling to glutaminase contributes to cellular transformation
► Glutaminase activity is enhanced in cancer cells, independent of protein expression
► Allosteric inhibitors of glutaminase selectively inhibit cancer cell growth