Troglitazone exerts metabolic and antitumor effects on T47D breast cancer cells by suppressing mitochondrial pyruvate availability

Jung,Kyung‑Ho; Lee,Jin  Hee; Park,Jin‑Won; Moon,Seung‑Hwan; Cho,Young   Seok; Lee,Kyung‑Han

doi:10.3892/or.2019.7436

Troglitazone exerts metabolic and antitumor effects on T47D breast cancer cells by suppressing mitochondrial pyruvate availability

Authors:
- Kyung‑Ho Jung
- Jin Hee Lee
- Jin‑Won Park
- Seung‑Hwan Moon
- Young Seok Cho
- Kyung‑Han Lee
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Affiliations: Department of Nuclear Medicine, Samsung Medical Center, Seoul 135-710, Republic of Korea
Published online on: December 16, 2019 https://doi.org/10.3892/or.2019.7436
Pages: 711-717

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Abstract

The aim of the present study was to investigate the metabolic and anticancer effects of troglitazone (TGZ) with a focus on the potential role of mitochondrial pyruvate utilization. 2‑Deoxyglucose (2‑DG) was more cytotoxic in CT26 cancer cells compared with T47D cells, despite a smaller suppression of glucose uptake. On the other hand, TGZ caused a more prominent shift to glycolytic metabolism and was more cytotoxic in T47D cells. Both effects of TGZ on T47D cells were dose‑dependently reversed by addition of methyl pyruvate (mPyr), indicating suppression of mitochondrial pyruvate availability. Furthermore, UK5099, a specific mitochondrial pyruvate carrier inhibitor, closely simulated the metabolic and antitumor effects of TGZ and their reversal by mPyr. This was accompanied by a substantial reduction of activated p70S6K. In CT26 cells, UK5099 did not reduce activated p70S6K and only modestly decreased cell proliferation. In these cells, combining glutamine restriction with UK5099 further increased glucose uptake and completely suppressed cell proliferation. Thus, TGZ‑mediated inhibition of mitochondrial pyruvate utilization is an effective treatment for cancer cells that are more dependent on mitochondrial glucose metabolism. By contrast, cancer cells that are more glycolysis‑dependent may require suppression of glutamine utilization in addition to blocking mitochondrial pyruvate availability for a full antitumor effect.

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1	DeBerardinis RJ, Lum JJ, Hatzivassiliou G and Thompson CB: The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7:11–20. 2008. View Article : Google Scholar : PubMed/NCBI
2	Vander Heiden MG: Targeting cancer metabolism: A therapeutic window opens. Nat Rev Drug Discov. 10:671–684. 2011. View Article : Google Scholar : PubMed/NCBI
3	Farwell MD, Pryma DA and Mankoff DA: PET/CT imaging in cancer: Current applications and future directions. Cancer. 120:3433–3445. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kuntz S, Mazerbourg S, Boisbrun M, Cerella C, Diederich M, Grillier-Vuissoz I and Flament S: Energy restriction mimetic agents to target cancer cells: Comparison between 2-deoxyglucose and thiazolidinediones. Biochem Pharmacol. 92:102–111. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kim EH, Lee JH, Oh Y, Koh I, Shim JK, Park J, Choi J, Yun M, Jeon JY, Huh YM, et al: Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin. Neuro Oncol. 19:197–207. 2017.PubMed/NCBI
6	Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, Baudy AR, Hatzivassiliou G, Evangelista M and Settleman J: mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell. 29:548–562. 2016. View Article : Google Scholar : PubMed/NCBI
7	Swerdlow RH, E L, Aires D and Lu J: Glycolysis-respiration relationships in a neuroblastoma cell line. Biochim Biophys Acta. 1830:2891–2898. 2013. View Article : Google Scholar : PubMed/NCBI
8	Wei S, Kulp SK and Chen CS: Energy restriction as an antitumor target of thiazolidinediones. J Biol Chem. 285:9780–9791. 2010. View Article : Google Scholar : PubMed/NCBI
9	Mazerbourg S, Kuntz S, Grillier-Vuissoz I, Berthe A, Geoffroy M, Flament S, Bordessa A and Boisbrun M: Reprofiling of troglitazone towards more active and less toxic derivatives: A new hope for cancer treatment? Curr Top Med Chem. 16:2115–2124. 2016. View Article : Google Scholar : PubMed/NCBI
10	Moon SH, Lee SJ, Jung KH, Quach CH, Park JW, Lee JH, Cho YS and Lee KH: Troglitazone stimulates cancer cell uptake of 18F-FDG by suppressing mitochondrial respiration and augments sensitivity to glucose restriction. J Nucl Med. 57:129–135. 2016. View Article : Google Scholar : PubMed/NCBI
11	Shannon CE, Daniele G, Galindo C, Abdul-Ghani MA, DeFronzo RA and Norton L: Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS J. 284:451–465. 2017. View Article : Google Scholar : PubMed/NCBI
12	Vacanti NM, Divakaruni AS, Green CR, Parker SJ, Henry RR, Ciaraldi TP, Murphy AN and Metallo CM: Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol Cell. 56:425–435. 2014. View Article : Google Scholar : PubMed/NCBI
13	Reitzer LJ, Wice BM and Kennell D: Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 254:2669–2676. 1979.PubMed/NCBI
14	Yuneva M, Zamboni N, Oefner P, Sachidanandam R and Lazebnik Y: Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 178:93–105. 2007. View Article : Google Scholar : PubMed/NCBI
15	Takeuchi Y, Nakayama Y, Fukusaki E and Irino Y: Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion. Biochem Biophys Res Commun. 495:761–767. 2018. View Article : Google Scholar : PubMed/NCBI
16	Vichai V and Kirtikara K: Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 1:1112–1116. 2006. View Article : Google Scholar : PubMed/NCBI
17	Rampelt H and van der Laan M: Metabolic remodeling: A pyruvate transport affair. EMBO J. 34:835–837. 2015. View Article : Google Scholar : PubMed/NCBI
18	Corbet C, Bastien E, Draoui N, Doix B, Mignion L, Jordan BF, Marchand A, Vanherck JC, Chaltin P, Schakman O, et al: Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nat Commun. 9:12082018. View Article : Google Scholar : PubMed/NCBI
19	Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, Sudderth J, Calvaruso MA, Lumata L, Mitsche M, et al: Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 56:414–424. 2014. View Article : Google Scholar : PubMed/NCBI
20	Gibbons JJ, Abraham RT and Yu K: Mammalian target of rapamycin: Discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol. 36 (Suppl 3):S3–S17. 2009. View Article : Google Scholar : PubMed/NCBI
21	Hidalgo M and Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 19:6680–6686. 2000. View Article : Google Scholar : PubMed/NCBI