Show simple item record Hujber, Zoltán Petővári, Gábor Szoboszlai, Norbert Danko T Nagy, Noémi Kriston, Csilla Krencz, Ildikó Paku, Sándor Ozohanics, Olivér Drahos, László Jeney, András Sebestyén, Anna 2018-06-12T07:01:46Z 2018-06-12T07:01:46Z 2017
dc.identifier 85019979322
dc.identifier.citation pagination=74, pages: 12; journalVolume=36; journalIssueNumber=1; journalTitle=JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH;
dc.identifier.uri doi:10.1186/s13046-017-0544-y
dc.description.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.
dc.relation.ispartof urn:issn:0392-9078
dc.title Rapamycin (mTORC1 inhibitor) reduces the production of lactate and 2-hydroxyglutarate oncometabolites in IDH1 mutant fibrosarcoma cells
dc.type Journal Article 2018-06-05T12:13:54Z
dc.language.rfc3066 en
dc.identifier.mtmt 3241328
dc.identifier.wos 000403017600002
dc.identifier.pubmed 28578659
dc.contributor.department SE/AOK/I/I. Sz. Patológiai és Kísérleti Rákkutató Intézet
dc.contributor.institution Semmelweis Egyetem

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