Abstract
BackgroundMultiple 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.MethodsHT-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.ResultsRapamycin (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.ConclusionsConsidering 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.
Highlights
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
Translation, ribosome and mitochondrial biogenesis, autophagy, lipid biosynthesis are controlled by mTORC1, which phosphorylates e.g. Phospho70S6 kinase (p70S6K) and 4E-binding protein (4-EBP1) and other targets such as S6 which is a well-known marker of mTORC1 activity at protein level. mTORC2 phosphorylates e.g. v-akt murine thymoma viral oncogene homolog (Akt), Serum/glucocorticoid regulated kinase 1 (SGK1) and PKCα and enhances survival and cytoskeletal reorganization [3]
2-HG) in IDH1 mutant HT-1080 cells Characterising the dominant bioenergetic process in HT1080 fibrosarcoma cells increased glycolysis and impaired Tricarboxylic acid (TCA) cycle were observed in our previous study [33]. 2-HG production (Fig. 1a) – high level of this oncometabolite was detected by LC-MS – and the decreased number and irregular arrangement of the cristae in mitochondria represent other remarkable properties of HT-1080 cells
Summary
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. MTOR (mammalian target of rapamycin) orchestrates different pathways, influences cellular growth and metabolism. Mammalian target of rapamycin (mTOR) kinase represents an important regulator of cellular metabolism besides of its effects on cellular growth, protein synthesis, proliferation and survival. MTOR complexes orchestrate different pathways and based on their input influence cellular growth and metabolic programs. The multiple regulatory functions of mTOR complexes are achieved through different downstream targets. The failures in PI3K/Akt/mTOR signalling pathway and hyperactivated mTOR kinase have been described in many tumours. A correlation between elevated mTOR activity – especially with potential high mTORC2 activity (mTORC2 complex related Rictor overexpression) – and poor clinical prognosis of different malignancies has been previously described in our and other studies [6,7,8]. Rapamycin (mTORC1 inhibitor) and its analogues (rapalogs; e.g. temsirolimus, everolimus) have been approved by FDA (Food and Drug Administration) and EMA (European Medicines Agency) in certain lymphomas, renal cell carcinomas, pancreatic and breast cancers; rapalogs and newly developing inhibitor phase studies are ongoing in many other malignancies
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