TY  - JOUR
A1  - Luger, Anna-Luisa
A1  - Lorenz, Nadja Irene
A1  - Urban, Hans
A1  - Divé, Iris
A1  - Engel, Anna Larissa
A1  - Strassheimer, Florian
A1  - Dettmer-Wilde, Katja
A1  - Zeiner, Pia Susan
A1  - Shaid, Shabnam
A1  - Struve, Nina
A1  - Kriegs, Malte
A1  - Hofmann, Ute
A1  - Oefner, Peter J.
A1  - Harter, Patrick Nikolaus
A1  - Steinbach, Joachim Peter
A1  - Ronellenfitsch, Michael Wilfried
T1  - Activation of epidermal growth factor receptor sensitizes glioblastoma cells to hypoxia-induced cell death
T2  - Cancers
N2  - 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.
KW  - glioblastoma
KW  - EGFR
KW  - EGFRvIII mutation
KW  - hypoxia
KW  - starvation
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55515
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-555154
SN  - 2072-6694
N1  - © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
VL  - 12
IS  - 8, art. 2144
SP  - 1
EP  - 14
PB  - MDPI
CY  - Basel
ER  -