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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

Rapamycin (mTORC1 inhibitor) reduces the production of lactate and 2-hydroxyglutarate oncometabolites in IDH1 mutant fibrosarcoma cells

Authors: Zoltán Hujber, Gábor Petővári, Norbert Szoboszlai, Titanilla Dankó, Noémi Nagy, Csilla Kriston, Ildikó Krencz, Sándor Paku, Olivér Ozohanics, László Drahos, András Jeney, Anna Sebestyén

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Multiple studies concluded that oncometabolites (e.g. D-2-hydroxyglutarate (2-HG) related to mutant isocitrate dehydrogenase 1/2 (IDH1/2) and lactate) have tumour promoting potential. Regulatory mechanisms implicated in the maintenance of oncometabolite production have great interest. mTOR (mammalian target of rapamycin) orchestrates different pathways, influences cellular growth and metabolism. Considering hyperactivation of mTOR in several malignancies, the question has been addressed whether mTOR operates through controlling of oncometabolite accumulation in metabolic reprogramming.

Methods

HT-1080 cells – carrying originally endogenous IDH1 mutation – were used in vitro and in vivo. Anti-tumour effects of rapamycin were studied using different assays. The main sources and productions of the oncometabolites (2-HG and lactate) were analysed by 13C-labeled substrates. Alterations at protein and metabolite levels were followed by Western blot, flow cytometry, immunohistochemistry and liquid chromatography mass spectrometry using rapamycin, PP242 and different glutaminase inhibitors, as well.

Results

Rapamycin (mTORC1 inhibitor) inhibited proliferation, migration and altered the metabolic activity of IDH1 mutant HT-1080 cells. Rapamycin reduced the level of 2-HG sourced mainly from glutamine and glucose derived lactate which correlated to the decreased incorporation of 13C atoms from 13C-substrates. Additionally, decreased expressions of lactate dehydrogenase A and glutaminase were also observed both in vitro and in vivo.

Conclusions

Considering the role of lactate and 2-HG in regulatory network and in metabolic symbiosis it could be assumed that mTOR inhibitors have additional effects besides their anti-proliferative effects in tumours with glycolytic phenotype, especially in case of IDH1 mutation (e.g. acute myeloid leukemias, gliomas, chondrosarcomas). Based on our new results, we suggest targeting mTOR activity depending on the metabolic and besides molecular genetic phenotype of tumours to increase the success of therapies.
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Literature
1.
2.
Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155–62.CrossRefPubMed
3.
Albert V, Hall MN. mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol. 2015;33:55–66.CrossRefPubMed
4.
Zoncu R, Efeyan A, Sabatini DM. MTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.CrossRefPubMed
5.
Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13(5):1021–31.CrossRefPubMed
6.
Sticz T, Molnár A, Márk Á, Hajdu M, Nagy N, Végső G, et al. mTOR activity and its prognostic significance in human colorectal carcinoma depending on C1 and C2 complex-related protein expression. J Clin Pathol 2016 doi:10.​1136/​jclinpath-2016-203913.
7.
Bian Y, Wang Z, Xu J, Zhao W, Cao H, Zhang Z. Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer. Biochem Biophys Res Commun. 2015;464(2):534–40.CrossRefPubMed
8.
9.
Makinoshima H, Takita M, Saruwatari K, Umemura S, Obata Y, Ishii G, et al. Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma. J Biol Chem. 2015;290(28):17495–504.CrossRefPubMedPubMedCentral
10.
Yu L, Chen X, Wang L, Chen S. The sweet trap in tumors: aerobic glycolysis and potential targets for therapy. Oncotarget. 2016;7(25):38908–26.PubMedPubMedCentral
11.
12.
Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, et al. mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells. Cancer Cell. 2016;29(4):548–62.CrossRefPubMed
13.
Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, et al. Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest. 2015;4:1591–602.CrossRef
14.
Li J, Shin S, Sun Y, Yoon SO, Li C, Zhang E, et al. mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress. Cancer Res. 2016;76(16):4816–27.CrossRefPubMed
15.
Zha X, Sun Q, Zhang H. mTOR upregulation of glycolytic enzymes promotes tumor development. Cell Cycle. 2011;10(7):1015–6.CrossRefPubMed
16.
Van Hée VF, Pérez-Escuredo J, Cacace A, Copetti T, Sonveaux P. Lactate does not activate NF-κB in oxidative tumor cells. Front Pharmacol. 2015;6:228.PubMedPubMedCentral
17.
18.
Morin A, Letouzé E, Gimenez-Roqueplo AP, Favier J. Oncometabolites-driven tumorigenesis: From genetics to targeted therapy. Int J Cancer. 2014;135(10):2237–48.CrossRefPubMed
19.
Payen VL, Porporato PE, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci. 2016;73(7):1333–48.CrossRefPubMed
20.
Marchiq I, Pouysségur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J Mol Med (Berl). 2016;94:155–71.CrossRef
21.
22.
23.
24.
Chen JY, Lai YS, Tsai HJ, Kuo CC, Yen BL, Yeh SP, et al. The oncometabolite R-2 hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells. Sci Rep. 2016;6:32428.CrossRefPubMedPubMedCentral
25.
Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro-Oncology. 2016;18(1):16–26.CrossRefPubMed
26.
Esmaeili M, Hamans BC, Navis AC, van Horssen R, Bathen TF, Gribbestad IS, Leenders WP, Heerschap A. IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma. Cancer Res. 2014;74(17):4898–907.CrossRefPubMed
27.
Nagy N, Hajdu M, Márk Á, Király PA, Tóth M, Dankó T, et al. Growth inhibitory effect of rapamycin in Hodgkin-lymphoma cell lines characterized by constitutive NOTCH1 activation. Tumour Biol. 2016;37(10):13695–704.CrossRefPubMed
28.
Pogány G, Timár F, Oláh J, Harisi R, Polony G, Paku S, et al. Role of the basement membrane in tumor cell dormancy and cytotoxic resistance. Oncology. 2001;60(3):274–81.CrossRefPubMed
29.
Szoboszlai N, Guo X, Ozohanics O, Oláh J, Gömöry Á, Mihucz VG, et al. Determination of energy metabolites in cancer cells by porous graphitic carbon liquid chromatography electrospray ionization mass spectrometry for the assessment of energy metabolism. Anal Chim Acta. 2014;819:108–15.CrossRefPubMed
30.
Jaitz L, Mueller B, Koellensperger G, Huber D, Oburger E, Puschenreiter M, et al. LC-MS analysis of low molecular weight organic acids derived from root exudation. Anal Bioanal Chem. 2011;400(8):2587–96.CrossRefPubMed
31.
Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, et al. Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLoS One. 2015;10(9):e0133813.CrossRefPubMedPubMedCentral
32.
Krencz I, Sebestyén A, Fábián K, Márk Á, Moldvay J, Khoor A, et al. Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma. Hum Pathol 2016 doi:10.​1016/​j.​humpath.​2016.​12.​012. (Epub ahead of print).
33.
Jeney A, Hujber Z, Szoboszlai N, Fullár A, Oláh J, Pap É, et al. Characterisation of bioenergetic pathways and related regulators by multiple assays in human tumour cells. Cancer Cell Int. 2016;16:4.CrossRefPubMedPubMedCentral
34.
Elhammali A, Ippolito JE, Collins L, Crowley J, Marasa J, Piwnica-Worms D. A high-throughput fluorimetric assay for 2-hydroxyglutarate identifies Zaprinast as a glutaminase inhibitor. Cancer Discov. 2014;4(7):828–39.CrossRefPubMedPubMedCentral
35.
Gao X, Locasale JW. Serine metabolism links tumor suppression to the epigenetic landscape. Cell Metab. 2016;24(6):777–9.CrossRefPubMed
36.
Colvin H, Nishida N, Konno M, Haraguchi N, Takahashi H, Nishimura J, et al. Oncometabolite D-2-Hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci Rep. 2016;6:36289.CrossRefPubMedPubMedCentral
37.
Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537(7621):544–7.CrossRefPubMedPubMedCentral
38.
Li F, He X, Ye D, Lin Y, Yu H, Yao C, et al. NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol Cell. 2015;60(4):661–75.CrossRefPubMed
39.
Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016;539(7629):390–5.CrossRefPubMed
40.
41.
Chen X, Zhu Y, Wang Z, Zhu H, Pan Q, Su S, et al. mTORC1 alters the expression of glycolytic genes by regulating KPNA2 abundances. J Proteomics. 2016;136:13–24.CrossRefPubMed
42.
Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39(2):171–83.CrossRefPubMedPubMedCentral
43.
Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, et al. 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 2015;22(3):508–15.CrossRefPubMedPubMedCentral
44.
Carbonneau M, M Gagné L, Lalonde ME, Germain MA, Motorina A, Guiot MC, et al. 2-hydroxyglutarate activates the mTOR signalling pathway. Nat Commun. 2016;7:12700.CrossRefPubMedPubMedCentral
45.
Zhu H, Zhang Y, Chen J, Qiu J, Huang K, Wu M, et al. IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. PLoS One. 2017;12(1):e0169038.CrossRefPubMedPubMedCentral
46.
Tan P, Soo Tiong I, Fleming S, Pomilio G, Cummings N, Droogleever M, et al. The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study. Oncotarget. 2016. doi:10.​18632/​oncotarget.​13699. Epub ahead of print.
47.
Brenner AK, Andersson Tvedt TH, Bruserud Ø. The Complexity of Targeting PI3K-Akt-mTOR Signalling in Human Acute Myeloid Leukaemia: The Importance of Leukemic Cell Heterogeneity, Neighbouring Mesenchymal Stem Cells and Immunocompetent Cells. Molecules 2016;21(11).
48.
Miller JJ, Wen PY. Emerging targeted therapies for glioma. Expert Opin Emerg Drugs. 2016;21(4):441–52.CrossRefPubMed
49.
Becher OJ, Gilheeney SW, Khakoo Y, Lyden DC, Haque S, De Braganca KC, et al. A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors. Pediatr Blood Cancer 2016 doi: 10.​1002/​pbc.​26409. (Epub ahead of print).
50.
Zhao X, Jiang P, Deng X, Li Z, Tian F, Guo F, et al. Inhibition of mTORC1 signaling sensitizes hepatocellular carcinoma cells to glycolytic stress. Am J Cancer Res. 2016;6(10):2289–98.PubMedPubMedCentral
51.
Chen L, Cui H, Fang J, Deng H, Kuang P, Guo H, et al. Glutamine deprivation plus BPTES alters etoposide- and cisplatin-induced apoptosis in triple negative breast cancer cells. Oncotarget. 2016;7(34):54691–701.PubMedPubMedCentral
52.
53.
Allen E, Miéville P, Warren CM, Saghafinia S, Li L, Peng MW, et al. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling. Cell Rep. 2016;15(6):1144–60.CrossRefPubMedPubMedCentral
Metadata
Title
Rapamycin (mTORC1 inhibitor) reduces the production of lactate and 2-hydroxyglutarate oncometabolites in IDH1 mutant fibrosarcoma cells
Authors
Zoltán Hujber
Gábor Petővári
Norbert Szoboszlai
Titanilla Dankó
Noémi Nagy
Csilla Kriston
Ildikó Krencz
Sándor Paku
Olivér Ozohanics
László Drahos
András Jeney
Anna Sebestyén
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0544-y

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