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Koch, Katharina [Author]; Hartmann, Rudolf [Author]; Suwala, Abigail Kora [Author]; Herrera Rios, Dayana [Author]; Kamp, Marcel [Author]; Sabel, Michael [Author]; Steiger, Hans-Jakob [Author]; Willbold, Dieter [Author]; Sharma, Amit Sharma [Author]; Kahlert, Ulf D. [Author]; Maciaczyk, Jarek [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 [VerfasserIn]; Hartmann, Rudolf [VerfasserIn]; Suwala, Abigail Kora [VerfasserIn]; Herrera Rios, Dayana [VerfasserIn]; Kamp, Marcel [VerfasserIn]; Sabel, Michael [VerfasserIn]; Steiger, Hans-Jakob [VerfasserIn]; Willbold, Dieter [VerfasserIn]; Sharma, Amit Sharma [VerfasserIn]; Kahlert, Ulf D. [VerfasserIn]; Maciaczyk, Jarek [VerfasserIn]
  • imprint: 29 November 2021
  • Published in: Cancers ; 13(2021), 23, Artikel-ID 6001, Seite 1-17
  • Language: English
  • DOI: 10.3390/cancers13236001
  • ISSN: 2072-6694
  • Identifier:
  • Keywords: cancer stem cells ; glioblastoma ; glutamine ; metabolism ; NMR spectroscopy ; oncometabolites ; xCT ; ZEB1
  • Origination:
  • Footnote:
  • 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