Overexpression of cystine/glutamate antiporter xCT correlates with nutrient flexibility and ZEB1 expression in highly clonogenic glioblastoma stem-like cells (GSCs)

• Verfasst von: Koch, Katharina [VerfasserIn]
• Verfasst von: Hartmann, Rudolf [VerfasserIn]
• Verfasst von: Suwala, Abigail Kora [VerfasserIn]
• Verfasst von: Herrera Rios, Dayana [VerfasserIn]
• Verfasst von: Kamp, Marcel [VerfasserIn]
• Verfasst von: Sabel, Michael [VerfasserIn]
• Verfasst von: Steiger, Hans-Jakob [VerfasserIn]
• Verfasst von: Willbold, Dieter [VerfasserIn]
• Verfasst von: Sharma, Amit Sharma [VerfasserIn]
• Verfasst von: Kahlert, Ulf D. [VerfasserIn]
• Verfasst von: Maciaczyk, Jarek [VerfasserIn]
• Titel: Overexpression of cystine/glutamate antiporter xCT correlates with nutrient flexibility and ZEB1 expression in highly clonogenic glioblastoma stem-like cells (GSCs)
• Verf.angabe: 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
• E-Jahr: 2021
• Jahr: 29 November 2021
• Umfang: 17 S.
• Fussnoten: Gesehen am 20.04.2022
• Titel Quelle: Enthalten in: Cancers
• Ort Quelle: Basel : MDPI, 2009
• Jahr Quelle: 2021
• Band/Heft Quelle: 13(2021), 23, Artikel-ID 6001, Seite 1-17
• ISSN Quelle: 2072-6694
• DOI: doi:10.3390/cancers13236001
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cancer stem cells
• Sach-SW: glioblastoma
• Sach-SW: glutamine
• Sach-SW: metabolism
• Sach-SW: NMR spectroscopy
• Sach-SW: oncometabolites
• Sach-SW: xCT
• Sach-SW: ZEB1
• K10plus-PPN: 1782364854

Abstract

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.