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Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

  • Miriam R. Reynolds and Brian F. Clem EMAIL logo
Published/Copyright: April 10, 2015
Biological Chemistry
From the journal Biological Chemistry Volume 396 Issue 8

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.

Keywords: anaplerosis; cancer; c-Myc; glutaminolysis; thiazolidinediones; tumor
Corresponding author: Brian F. Clem, Department of Biochemistry and Molecular Genetics, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock St., CTRB, Louisville, KY 40202, USA, e-mail:

Acknowledgments

The authors gratefully acknowledge the laboratory of Dr. Levi Beverly for the kind gift of the mutant c-Myc lentiviral particles and Drs. Yoannis Imbert-Fernandez and Traci Kruer for their critical reading of the manuscript. NMR experiments were performed within the James Graham Brown Cancer Center NMR facility, supported in part by the Brown Foundation and P20GM103482. This work was supported by a Center of Biomedical Research Excellence in Molecular Targets (P20GM103482-10) and CA166327 (BFC) from the National Institutes of Health.

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Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2014-0307) offers supplementary material, available to authorized users.

Received: 2014-12-10
Accepted: 2015-4-2
Published Online: 2015-4-10
Published in Print: 2015-8-1

©2015 by De Gruyter

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https://doi.org/10.1515/hsz-2014-0307
Keywords for this article
anaplerosis; cancer; c-Myc; glutaminolysis; thiazolidinediones; tumor

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Ras activation revisited: role of GEF and GAP systems
  4. When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding
  5. Cathepsin S: therapeutic, diagnostic, and prognostic potential
  6. Minireview
  7. Overview of the roles of Sox2 in stem cell and development
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Transcriptional and translational mechanisms contribute to regulate the expression of Discs Large 1 protein during different biological processes
  11. Membranes, Lipids, Glycobiology
  12. Rapid transfer of overexpressed integral membrane protein from the host membrane into soluble lipid nanodiscs without previous purification
  13. Molecular Medicine
  14. Characterization of a new dual-targeting fully human antibody with potent antitumor activity against nasopharyngeal carcinoma
  15. Cell Biology and Signaling
  16. Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres
  17. SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A
  18. Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism
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