Overexpression of cystine/glutamate antiporter xCT correlates with nutrient flexibility and ZEB1 expression in highly clonogenic glioblastoma stem-like cells (GSCs)
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 resonanc...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
29 November 2021
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| In: |
Cancers
Year: 2021, Volume: 13, Issue: 23, Pages: 1-17 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers13236001 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/cancers13236001 Verlag, kostenfrei, Volltext: https://www.mdpi.com/2072-6694/13/23/6001 
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| Author Notes: | Katharina Koch, Rudolf Hartmann, Abigail Kora Suwala, Dayana Herrera Rios, Marcel Alexander Kamp, Michael Sabel, Hans-Jakob Steiger, Dieter Willbold, Amit Sharma, Ulf Dietrich Kahlert and Jarek Maciaczyk |
| Summary: | 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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| Item Description: | Gesehen am 20.04.2022 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers13236001 |