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Title: Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation
Authors: Goji, Takeo
Takahara, Kazuhiko  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-4730-8187 (unconfirmed)
Negisjhi, Manabu
Katoh, Hironori  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-8191-8117 (unconfirmed)
Author's alias: 高原, 和彦
根岸, 学
加藤, 裕教
Keywords: amino acid transport
cell death
glioblastoma
glucose
reactive oxygen species (ROS)
cystine
Issue Date: 1-Dec-2017
Publisher: American Society for Biochemistry and Molecular Biolog (ASBMB)
Journal title: Journal of Biological Chemistry
Volume: 292
Issue: 48
Start page: 19721
End page: 19732
Abstract: Oncogenic signaling in cancer cells alters glucose uptake and utilization to supply sufficient energy and biosynthetic intermediates for survival and sustained proliferation. Oncogenic signaling also prevents oxidative stress and cell death caused by increased production of reactive oxygen species. However, elevated glucose metabolism in cancer cells, especially in glioblastoma, results in the cells becoming sensitive to glucose deprivation (i.e. in high glucose dependence), which rapidly induces cell death. However, the precise mechanism of this type of cell death remains unknown. Here, we report that glucose deprivation alone does not trigger glioblastoma cell death. We found that, for cell death to occur in glucose-deprived glioblastoma cells, cystine and glutamine also need to be present in culture media. We observed that cystine uptake through the cystine/glutamate antiporter xCT under glucose deprivation rapidly induces NADPH depletion, reactive oxygen species accumulation, and cell death. We conclude that although cystine uptake is crucial for production of antioxidant glutathione in cancer cells its transport through xCT also induces oxidative stress and cell death in glucose-deprived glioblastoma cells. Combining inhibitors targeting cancer-specific glucose metabolism with cystine and glutamine treatment may offer a therapeutic approach for glioblastoma tumors exhibiting high xCT expression.
Rights: This research was originally published in the Journal of Biological Chemistry. [Takeo Goji, Kazuhiko Takahara, Manabu Negishi, Hironori Katoh.Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation. J. Biol. Chem. 2017; 292:19721-19732]. © the American Society for Biochemistry and Molecular Biology.
The full-text file will be made open to the public on 1 December 2018 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
URI: http://hdl.handle.net/2433/231984
DOI(Published Version): 10.1074/jbc.M117.814392
PubMed ID: 29038291
Appears in Collections:Journal Articles

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