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Koch, Katharina [Author]; Hartmann, Rudolf [Author]; Maciaczyk, Jarek [Author]; Suwala, Abigail Kora [Author]; Rios, Dayana Herrera [Author]; Kamp, Marcel Alexander [Author]; Sabel, Michael [Author]; Steiger, Hans-Jakob [Author]; Willbold, Dieter [Author]; Sharma, Amit [Author]; Kahlert, Ulf Dietrich [Author]

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)

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  • Media type: E-Article
  • Title: Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)
  • Contributor: Koch, Katharina [Author]; Hartmann, Rudolf [Author]; Maciaczyk, Jarek [Author]; Suwala, Abigail Kora [Author]; Rios, Dayana Herrera [Author]; Kamp, Marcel Alexander [Author]; Sabel, Michael [Author]; Steiger, Hans-Jakob [Author]; Willbold, Dieter [Author]; Sharma, Amit [Author]; Kahlert, Ulf Dietrich [Author]
  • imprint: MDPI, 2021
  • Published in: Cancers 13(23), 6001 - (2021). doi:10.3390/cancers13236001
  • Language: English
  • DOI: https://doi.org/10.3390/cancers13236001
  • ISSN: 2072-6694
  • Origination:
  • Footnote: Diese Datenquelle enthält auch Bestandsnachweise, die nicht zu einem Volltext führen.
  • Description: 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.
  • Access State: Open Access