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Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

  • Miriam R. Reynolds und Brian F. Clem EMAIL logo
Veröffentlicht/Copyright: 10. April 2015
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 396 Heft 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.

References

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, 1046–1058.10.4161/cbt.11.12.15709Suche in Google Scholar PubMed PubMed Central

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, 929052.10.1155/2012/929052Suche in Google Scholar PubMed PubMed Central

Bost, F., Sahra, I.B., Le Marchand-Brustel, Y., and Tanti, J.F. (2012). Metformin and cancer therapy. Curr. Opin. Oncol. 24, 103–108.10.1097/CCO.0b013e32834d8155Suche in Google Scholar PubMed

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, 1661–1670.10.1016/j.freeradbiomed.2007.02.009Suche in Google Scholar PubMed

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–E737.10.1152/ajpendo.00485.2001Suche in Google Scholar PubMed

DeBerardinis, R.J. and Cheng, T. (2009). Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324.10.1038/onc.2009.358Suche in Google Scholar PubMed PubMed Central

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, 19345–19350.10.1073/pnas.0709747104Suche in Google Scholar PubMed PubMed Central

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, 3951–3956.10.1073/pnas.96.7.3951Suche in Google Scholar PubMed PubMed Central

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, 247–251.10.1016/j.exphem.2013.12.001Suche in Google Scholar PubMed

Estrela, J.M., Ortega, A., and Obrador, E. (2006). Glutathione in cancer biology and therapy. Crit. Rev. Clin. Lab. Sci. 43, 143–181.10.1080/10408360500523878Suche in Google Scholar PubMed

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, 4429–4438.10.1158/0008-5472.CAN-13-0080Suche in Google Scholar PubMed PubMed Central

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, 511–519.10.1002/jcp.22360Suche in Google Scholar PubMed

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, 1688–1697.10.1136/gut.2003.031997Suche in Google Scholar PubMed PubMed Central

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, 1039–1049.10.1517/13543784.15.9.1039Suche in Google Scholar PubMed

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, 762–765.10.1038/nature07823Suche in Google Scholar PubMed PubMed Central

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, 890–901.10.1158/1535-7163.MCT-13-0870Suche in Google Scholar PubMed

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, 867–872.10.1056/NEJM199803263381303Suche in Google Scholar PubMed

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.Suche in Google 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.Suche in 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, 110–121.10.1016/j.cmet.2011.12.009Suche in Google Scholar PubMed PubMed Central

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, 6640–6650.10.1021/bi0159581Suche in Google Scholar PubMed

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, 12953–12956.10.1074/jbc.270.22.12953Suche in Google Scholar PubMed

Loi, C.M., Young, M., Randinitis, E., Vassos, A., and Koup, J.R. (1999). Clinical pharmacokinetics of troglitazone. Clin. Pharmacokinet. 37, 91–104.10.2165/00003088-199937020-00001Suche in 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, 514–534.10.2174/1566524011313040005Suche in 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, 10990–10995.10.1073/pnas.180329197Suche in Google 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, 1203–1210.10.2337/diab.43.10.1203Suche in Google 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, 827–831.10.2337/diabetes.49.5.827Suche in 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, 2669–2676.10.1016/S0021-9258(17)30124-2Suche in 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, 556–566.10.1038/onc.2012.635Suche in Google Scholar PubMed PubMed Central

Routh, R., McCarthy, K., and Welbourne, T. (2002). Troglitazone inhibits glutamine metabolism in rat mesangial cells. Am. J. Physiol. Endocrinol. Metab. 282, E231–E238.10.1152/ajpendo.2002.282.1.E231Suche in Google Scholar PubMed

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, 363–372.10.1046/j.1463-1326.2000.00099.xSuche in Google Scholar PubMed

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, 101–105.10.1038/nature12040Suche in Google Scholar PubMed PubMed Central

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, 650–661.10.1016/j.cmet.2014.08.003Suche in 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, 135–139.10.1016/S0014-5793(99)00871-6Suche in 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, 7022–7030.10.1158/1078-0432.CCR-04-0879Suche in Google Scholar PubMed

Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.10.1126/science.123.3191.309Suche in Google Scholar PubMed

Wise, D.R. and Thompson, C.B. (2010). Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433.10.1016/j.tibs.2010.05.003Suche in Google Scholar PubMed PubMed Central

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, 18782–18787.10.1073/pnas.0810199105Suche in Google Scholar PubMed PubMed Central

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, 1087–1092.10.2337/diab.44.9.1087Suche in Google Scholar PubMed

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, 93–105.10.1083/jcb.200703099Suche in Google Scholar PubMed PubMed Central

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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  2. Reviews
  3. Ras activation revisited: role of GEF and GAP systems
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  10. Transcriptional and translational mechanisms contribute to regulate the expression of Discs Large 1 protein during different biological processes
  11. Membranes, Lipids, Glycobiology
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https://doi.org/10.1515/hsz-2014-0307
Schlagwörter für diesen Artikel
anaplerosis; cancer; c-Myc; glutaminolysis; thiazolidinediones; tumor

Artikel in diesem Heft

  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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