MTORC1 activation sensitizes human glioma cells to hypoxia-induced cell death
Anna-Luisa Thiepold1, Nadja I. Lorenz1, Martha Foltyn1, Anna L. Engel1, Iris Divé1, Hans Urban1, Sonja Heller1, Ines Bruns1 , Ute Hofmann2, Stefan Dröse3, Patrick N. Harter4, Michel Mittelbronn4, Joachim P. Steinbach1 and Michael W. Ronellenfitsch1
1Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Germany
3Department of Anaesthesiology, University Hospital Frankfurt, Frankfurt am Main, Germany.
4Edinger-Institute, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from epidermal growth factor receptor (EGFR) via mTORC1 is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways. Therefore, EGFR and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that EGFR 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 (PPP). Mechanistically, mTORC1 upregulated glucose 6-phosphate dehydrogenase. 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 PGC-1-α 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 patient cohorts more likely to benefit from hypoxia-inducing therapies in future clinical evaluations.