Activation of epidermal growth factor receptor sensitizes glioblastoma cells to hypoxia-induced cell death

  • 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 EGFRvIII as 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, EGFRvIII mutant 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.
Author:Anna-Luisa LugerORCiD, Nadja Irene LorenzGND, Hans UrbanGND, Iris DivéGND, Anna Larissa EngelGND, Florian Strassheimer, Katja Dettmer-WildeORCiDGND, Pia Susan ZeinerORCiD, Shabnam ShaidGND, Nina Struve, Malte Kriegs, Ute HofmannORCiD, Peter J. Oefner, Patrick Nikolaus HarterORCiDGND, Joachim Peter SteinbachORCiDGND, Michael Wilfried RonellenfitschORCiDGND
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/08/03
Date of first Publication:2020/08/03
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/09/10
Tag:EGFR; EGFRvIII mutation; glioblastoma; hypoxia; starvation
Issue:8, art. 2144
Page Number:14
First Page:1
Last Page:14
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Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0