TY  - JOUR
AU  - Koch, Katharina
AU  - Hartmann, Rudolf
AU  - Suwala, Abigail Kora
AU  - Rios, Dayana Herrera
AU  - Kamp, Marcel Alexander
AU  - Sabel, Michael
AU  - Steiger, Hans-Jakob
AU  - Willbold, Dieter
AU  - Sharma, Amit
AU  - Kahlert, Ulf Dietrich
AU  - Maciaczyk, Jarek
TI  - Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)
JO  - Cancers
VL  - 13
IS  - 23
SN  - 2072-6694
CY  - Basel
PB  - MDPI
M1  - FZJ-2021-04713
SP  - 6001 -
PY  - 2021
AB  - Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
LB  - PUB:(DE-HGF)16
C6  - 34885110
UR  - <Go to ISI:>//WOS:000762087200001
DO  - DOI:10.3390/cancers13236001
UR  - https://juser.fz-juelich.de/record/902967
ER  -