title: Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Wang
authors.forename: Jon W
authors.initials: JW
authors.lastname: Erickson
authors.forename: Reina
authors.initials: R
authors.lastname: Fuji
authors.forename: Sekar
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Ramani
authors.initials: R
authors.lastname: Dinavahi
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Wilson
authors.forename: Andre L B
authors.initials: AL
authors.lastname: Ambrosio
authors.forename: Sandra M G
authors.initials: SM
authors.lastname: Dias
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005972:Glutaminase; D020741:rho GTP-Binding Proteins