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| 100 | 1 | _ | |a Koch, Katharina |0 0000-0002-9994-6204 |b 0 |
| 245 | _ | _ | |a Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs) |
| 260 | _ | _ | |a Basel |c 2021 |b MDPI |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a 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. |
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| 700 | 1 | _ | |a Hartmann, Rudolf |0 P:(DE-Juel1)132001 |b 1 |
| 700 | 1 | _ | |a Suwala, Abigail Kora |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Rios, Dayana Herrera |0 P:(DE-HGF)0 |b 3 |
| 700 | 1 | _ | |a Kamp, Marcel Alexander |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Sabel, Michael |0 P:(DE-Juel1)165921 |b 5 |
| 700 | 1 | _ | |a Steiger, Hans-Jakob |0 P:(DE-HGF)0 |b 6 |
| 700 | 1 | _ | |a Willbold, Dieter |0 P:(DE-Juel1)132029 |b 7 |
| 700 | 1 | _ | |a Sharma, Amit |0 0000-0002-2216-5389 |b 8 |
| 700 | 1 | _ | |a Kahlert, Ulf Dietrich |0 0000-0002-6021-1841 |b 9 |
| 700 | 1 | _ | |a Maciaczyk, Jarek |0 P:(DE-HGF)0 |b 10 |e Corresponding author |
| 773 | _ | _ | |a 10.3390/cancers13236001 |g Vol. 13, no. 23, p. 6001 - |0 PERI:(DE-600)2527080-1 |n 23 |p 6001 - |t Cancers |v 13 |y 2021 |x 2072-6694 |
| 856 | 4 | _ | |u https://juser.fz-juelich.de/record/902967/files/cancers-13-06001.pdf |y OpenAccess |
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