Luger, Anna-Luisa and Lorenz, Nadja and Urban, Hans and Dive, Iris and Engel, Anna L. and Strassheimer, Florian and Dettmer, Katja and Zeiner, Pia S. and Shaid, Shabnam and Struve, Nina and Kriegs, Malte and Hofmann, Ute and Oefner, Peter J. and Harter, Patrick N. and Steinbach, Joachim P. and Ronellenfitsch, Michael W. (2020) Activation of Epidermal Growth Factor Receptor Sensitizes Glioblastoma Cells to Hypoxia-Induced Cell Death. CANCERS, 12 (8): 2144. ISSN , 2072-6694
Full text not available from this repository. (Request a copy)Abstract
Background: The epidermal growth factor receptor (EGFR) signaling pathway is genetically activated in approximately 50% of glioblastomas (GBs). Its inhibition has been explored clinically but produced disappointing results, potentially due to metabolic effects that protect GB cells against nutrient deprivation and hypoxia. Here, we hypothesized that EGFR activation could disable metabolic adaptation and define a GB cell population sensitive to starvation. Methods: Using genetically engineered GB cells to model different types of EGFR activation, we analyzed changes in metabolism and cell survival under conditions of the tumor microenvironment. Results: We found that expression of mutant EGFRvIIIas well as EGF stimulation of EGFR-overexpressing cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. This was preceded by adenosine triphosphate (ATP) depletion and an increase in glycolysis. Furthermore, EGFRvIIImutant cells had higher levels of mitochondrial superoxides potentially due to decreased metabolic flux into the serine synthesis pathway which was associated with a decrease in the NADPH/NADP+ ratio. Conclusions: The finding that EGFR activation renders GB cells susceptible to starvation could help to identify a subgroup of patients more likely to benefit from starvation-inducing therapies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NEWLY-DIAGNOSED GLIOBLASTOMA; MALIGNANT GLIOMA-CELLS; MAMMALIAN TARGET; PHASE-II; TEMOZOLOMIDE; RADIOTHERAPY; BEVACIZUMAB; RAPAMYCIN; EGFRVIII; COMBINATION; glioblastoma; EGFR; EGFRvIIImutation; hypoxia; starvation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Mar 2021 09:47 |
| Last Modified: | 17 Mar 2021 09:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44071 |
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