Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

See all formats and pricing
More options …
Volume 396, Issue 8


Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Miriam R. Reynolds
  • Department of Biochemistry and Molecular Genetics, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock St., CTRB, Louisville, KY 40202, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Brian F. Clem
  • Corresponding author
  • Department of Biochemistry and Molecular Genetics, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock St., CTRB, Louisville, KY 40202, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-04-10 | DOI: https://doi.org/10.1515/hsz-2014-0307


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.

This article offers supplementary material which is provided at the end of the article.

Keywords: anaplerosis; cancer; c-Myc; glutaminolysis; thiazolidinediones; tumor


  • Akinyeke, T.O. and Stewart, L.V. (2011). Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARg-independent mechanism. Cancer Biol. Ther. 11, 1046–1058.Web of ScienceGoogle Scholar

  • Bolden, A., Bernard, L., Jones, D., Akinyeke, T., and Stewart, L.V. (2012). The PPARg agonist troglitazone regulates Erk 1/2 phosphorylation via a PPARg-independent, MEK-dependent pathway in human prostate cancer cells. PPAR Res. 2012, 929052.CrossrefWeb of ScienceGoogle Scholar

  • Bost, F., Sahra, I.B., Le Marchand-Brustel, Y., and Tanti, J.F. (2012). Metformin and cancer therapy. Curr. Opin. Oncol. 24, 103–108.Google Scholar

  • Cerbone, A., Toaldo, C., Laurora, S., Briatore, F., Pizzimenti, S., Dianzani, M.U., Ferretti, C., and Barrera, G. (2007). 4-Hydroxynonenal and PPARg ligands affect proliferation, differentiation, and apoptosis in colon cancer cells. Free Radic. Biol. Med. 42, 1661–1670.Web of ScienceGoogle Scholar

  • Coates, G., Nissim, I., Battarbee, H., and Welbourne, T. (2002). Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells. Am. J. Physiol. Endocrinol. Metab. 283, E729–E737.Google Scholar

  • DeBerardinis, R.J. and Cheng, T. (2009). Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324.Web of ScienceGoogle Scholar

  • DeBerardinis, R.J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., and Thompson, C.B. (2007). Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. USA 104, 19345–19350.Web of ScienceCrossrefGoogle Scholar

  • Demetri, G.D., Fletcher, C.D., Mueller, E., Sarraf, P., Naujoks, R., Campbell, N., Spiegelman, B.M., and Singer, S. (1999). Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-g ligand troglitazone in patients with liposarcoma. Proc. Natl. Acad. Sci. USA 96, 3951–3956.CrossrefGoogle Scholar

  • Emadi, A., Jun, S.A., Tsukamoto, T., Fathi, A.T., Minden, M.D., and Dang, C.V. (2014). Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp. Hematol. 42, 247–251.Web of ScienceGoogle Scholar

  • Estrela, J.M., Ortega, A., and Obrador, E. (2006). Glutathione in cancer biology and therapy. Crit. Rev. Clin. Lab. Sci. 43, 143–181.PubMedCrossrefGoogle Scholar

  • Fendt, S.M., Bell, E.L., Keibler, M.A., Davidson, S.M., Wirth, G.J., Fiske, B., Mayers, J.R., Schwab, M., Bellinger, G., Csibi, A., et al. (2013). Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 73, 4429–4438.Web of ScienceGoogle Scholar

  • Friday, E., Oliver, R., 3rd, Welbourne, T., and Turturro, F. (2011). Glutaminolysis and glycolysis regulation by troglitazone in breast cancer cells: relationship to mitochondrial membrane potential. J. Cell Physiol. 226, 511–519.Web of ScienceGoogle Scholar

  • Galli, A., Ceni, E., Crabb, D.W., Mello, T., Salzano, R., Grappone, C., Milani, S., Surrenti, E., Surrenti, C., and Casini, A. (2004). Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARg independent mechanisms. Gut 53, 1688–1697.Google Scholar

  • Galli, A., Mello, T., Ceni, E., Surrenti, E., and Surrenti, C. (2006). The potential of antidiabetic thiazolidinediones for anticancer therapy. Exp. Opin. Invest. Drugs 15, 1039–1049.Google Scholar

  • Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., et al. (2009). c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765.Web of ScienceGoogle Scholar

  • Gross, M.I., Demo, S.D., Dennison, J.B., Chen, L., Chernov-Rogan, T., Goyal, B., Janes, J.R., Laidig, G.J., Lewis, E.R., Li, J., et al. (2014). Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901.Google Scholar

  • Inzucchi, S.E., Maggs, D.G., Spollett, G.R., Page, S.L., Rife, F.S., Walton, V., and Shulman, G.I. (1998). Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 338, 867–872.Google Scholar

  • Kim, T.A., Kang, J.M., Hyun, J.S., Lee, B., Kim, S.J., Yang, E.S., Hong, S., Lee, H.J., Fujii, M., Niederhuber, J.E., et al. (2014). The Smad7-Skp2 complex orchestrates Myc stability, impacting on the cytostatic effect of TGF-b. J. Cell Sci. 127, 411–421.Web of ScienceGoogle Scholar

  • Kubota, T., Koshizuka, K., Williamson, E.A., Asou, H., Said, J.W., Holden, S., Miyoshi, I., and Koeffler, H.P. (1998). Ligand for peroxisome proliferator-activated receptor g (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 58, 3344–3352.Google Scholar

  • Le, A., Lane, A.N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C.J., Slusher, B.S., Zhang, H., et al. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 15, 110–121.Google Scholar

  • Leesnitzer, L.M., Parks, D.J., Bledsoe, R.K., Cobb, J.E., Collins, J.L., Consler, T.G., Davis, R.G., Hull-Ryde, E.A., Lenhard, J.M., Patel, L., et al. (2002). Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41, 6640–6650.Google Scholar

  • Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., and Kliewer, S.A. (1995). An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR g). J. Biol. Chem. 270, 12953–12956.Google Scholar

  • Loi, C.M., Young, M., Randinitis, E., Vassos, A., and Koup, J.R. (1999). Clinical pharmacokinetics of troglitazone. Clin. Pharmacokinet. 37, 91–104.Google Scholar

  • Mates, J.M., Segura, J.A., Martin-Rufian, M., Campos-Sandoval, J.A., Alonso, F.J., and Marquez, J. (2013). Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. Curr. Mol. Med. 13, 514–534.Google Scholar

  • Mueller, E., Smith, M., Sarraf, P., Kroll, T., Aiyer, A., Kaufman, D.S., Oh, W., Demetri, G., Figg, W.D., Zhou, X.P., et al. (2000). Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc. Natl. Acad. Sci. USA 97, 10990–10995.CrossrefGoogle Scholar

  • Oakes, N.D., Kennedy, C.J., Jenkins, A.B., Laybutt, D.R., Chisholm, D.J., and Kraegen, E.W. (1994). A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat. Diabetes 43, 1203–1210.CrossrefPubMedGoogle Scholar

  • Petersen, K.F., Krssak, M., Inzucchi, S., Cline, G.W., Dufour, S., and Shulman, G.I. (2000). Mechanism of troglitazone action in type 2 diabetes. Diabetes 49, 827–831.Google Scholar

  • Reitzer, L.J., Wice, B.M., and Kennell, D. (1979). Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 254, 2669–2676.Google Scholar

  • Reynolds, M.R., Lane, A.N., Robertson, B., Kemp, S., Liu, Y., Hill, B.G., Dean, D.C., and Clem, B.F. (2014). Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 33, 556–566.Web of ScienceGoogle Scholar

  • Routh, R., McCarthy, K., and Welbourne, T. (2002). Troglitazone inhibits glutamine metabolism in rat mesangial cells. Am. J. Physiol. Endocrinol. Metab. 282, E231–E238.Google Scholar

  • Smith, S.A., Lister, C.A., Toseland, C.D., and Buckingham, R.E. (2000). Rosiglitazone prevents the onset of hyperglycaemia and proteinuria in the zucker diabetic fatty rat. Diabetes Obes. Metab. 2, 363–372.Google Scholar

  • Son, J., Lyssiotis, C.A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R.M., Ferrone, C.R., Mullarky, E., Shyh-Chang, N., et al. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105.Web of ScienceGoogle Scholar

  • Srivastava, N., Kollipara, R.K., Singh, D.K., Sudderth, J., Hu, Z., Nguyen, H., Wang, S., Humphries, C.G., Carstens, R., Huffman, K.E., et al. (2014). Inhibition of cancer cell proliferation by PPARgamma is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab. 20, 650–661.Google Scholar

  • Takahashi, N., Okumura, T., Motomura, W., Fujimoto, Y., Kawabata, I., and Kohgo, Y. (1999). Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett. 455, 135–139.Google Scholar

  • Turturro, F., Friday, E., Fowler, R., Surie, D., and Welbourne, T. (2004). Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferator-activated receptor gamma-independent mechanism in breast cancer-derived cell lines. Clin. Cancer Res. 10, 7022–7030.Google Scholar

  • Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.Google Scholar

  • Wise, D.R. and Thompson, C.B. (2010). Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433.Web of ScienceGoogle Scholar

  • Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.Y., Pfeiffer, H.K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S.B., et al. (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. USA 105, 18782–18787.CrossrefGoogle Scholar

  • Young, P.W., Cawthorne, M.A., Coyle, P.J., Holder, J.C., Holman, G.D., Kozka, I.J., Kirkham, D.M., Lister, C.A., and Smith, S.A. (1995). Repeat treatment of obese mice with BRL 49653, a new potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. Diabetes 44, 1087–1092.CrossrefGoogle Scholar

  • Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., and Lazebnik, Y. (2007). Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J. Cell Biol. 178, 93–105.Google Scholar

About the article

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:

Received: 2014-12-10

Accepted: 2015-04-02

Published Online: 2015-04-10

Published in Print: 2015-08-01

Citation Information: Biological Chemistry, Volume 396, Issue 8, Pages 937–947, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0307.

Export Citation

©2015 by De Gruyter.Get Permission

Supplementary Article Materials

Comments (0)

Please log in or register to comment.
Log in