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000902967 1001_ $$00000-0002-9994-6204$$aKoch, Katharina$$b0
000902967 245__ $$aOverexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)
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000902967 520__ $$aCancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
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000902967 7001_ $$0P:(DE-Juel1)132001$$aHartmann, Rudolf$$b1
000902967 7001_ $$0P:(DE-HGF)0$$aSuwala, Abigail Kora$$b2
000902967 7001_ $$0P:(DE-HGF)0$$aRios, Dayana Herrera$$b3
000902967 7001_ $$0P:(DE-HGF)0$$aKamp, Marcel Alexander$$b4
000902967 7001_ $$0P:(DE-Juel1)165921$$aSabel, Michael$$b5
000902967 7001_ $$0P:(DE-HGF)0$$aSteiger, Hans-Jakob$$b6
000902967 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b7
000902967 7001_ $$00000-0002-2216-5389$$aSharma, Amit$$b8
000902967 7001_ $$00000-0002-6021-1841$$aKahlert, Ulf Dietrich$$b9
000902967 7001_ $$0P:(DE-HGF)0$$aMaciaczyk, Jarek$$b10$$eCorresponding author
000902967 773__ $$0PERI:(DE-600)2527080-1$$a10.3390/cancers13236001$$gVol. 13, no. 23, p. 6001 -$$n23$$p6001 -$$tCancers$$v13$$x2072-6694$$y2021
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