1. Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death.
- Author
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Thiepold AL, Lorenz NI, Foltyn M, Engel AL, Divé I, Urban H, Heller S, Bruns I, Hofmann U, Dröse S, Harter PN, Mittelbronn M, Steinbach JP, and Ronellenfitsch MW
- Subjects
- Cell Line, Tumor, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Glioma genetics, Glioma pathology, Glucose metabolism, Humans, Isocitrate Dehydrogenase genetics, Lactic Acid metabolism, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes genetics, Mutation genetics, Oxygen Consumption, PTEN Phosphohydrolase genetics, Reactive Oxygen Species metabolism, TOR Serine-Threonine Kinases genetics, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Cell Death drug effects, Cell Hypoxia physiology, Multiprotein Complexes metabolism, TOR Serine-Threonine Kinases metabolism
- Abstract
Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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