title: Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism.
abstract: Enhanced glutamine metabolism is required for tumor cell growth and survival, which suggests that agents targeting glutaminolysis may have utility within anti-cancer therapies. Troglitazone, a PPARγ agonist, exhibits significant anti-tumor activity and can alter glutamine metabolism in multiple cell types. Therefore, we examined whether troglitazone would disrupt glutamine metabolism in tumor cells and whether its action was reliant on PPARγ activity. We found that troglitazone treatment suppressed glutamine uptake and the expression of the glutamine transporter, ASCT2, and glutaminase. In addition, troglitazone reduced 13C-glutamine incorporation into the TCA cycle, decreased [ATP], and resulted in an increase in reactive oxygen species (ROS). Further, troglitazone treatment decreased tumor cell growth, which was partially rescued with the addition of the TCA-intermediate, α-ketoglutarate, or the antioxidant N-acetylcysteine. Importantly, troglitazone's effects on glutamine uptake or viable cell number were found to be PPARγ-independent. In contrast, troglitazone caused a decrease in c-Myc levels, while the proteasomal inhibitor, MG132, rescued c-Myc, ASCT2 and GLS1 expression, as well as glutamine uptake and cell number. Lastly, combinatorial treatment of troglitazone and metformin resulted in a synergistic decrease in cell number. Therefore, characterizing new anti-tumor properties of previously approved FDA therapies supports the potential for repurposing of these agents.
authors: Miriam R
authors: MR
authors: Reynolds
authors: Brian F
authors: BF
authors: Clem
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D005973:Glutamine; D000077288:Troglitazone