Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines

Okuno, Suzuka; Sato, Hiroki; Kuriyama-Matsumura, Kazumi; Tamba, Michiko; Wang, H; Sohda, Satoshi; Hamada, Hiromi; Yoshikawa, Hiroko; Kondo, Takahito; Bannai, Shiro

doi:10.1038/sj.bjc.6600786

Cited by 166 publications

(138 citation statements)

References 28 publications

(28 reference statements)

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“…The importance of the cystine/cysteine cycle for the resistance of cancer cells to chemotherapy has been recognized only recently (Okuno et al, 2003). Activation of the xCT gene in cancer cells by cytotoxic drugs may be a mechanism contributing to chemotherapy resistance in vivo, a possibility that apparently deserves further studies.…”

Section: Discussionmentioning

confidence: 99%

The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

et al. 2007

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The glutathione-dependent system is one of the key systems regulating cellular redox balance, and thus cell fate. Cysteine, typically present in its oxidized form cystine in the extracellular space, is regarded as the rate-limiting substrate for glutathione (GSH) synthesis. Cystine is transported into cells by the highly specific amino-acid antiporter system x c À . Since Burkitt's Lymphoma (BL) cells display limited uptake capacity for cystine, and are thus prone to oxidative stress-induced cell death, we stably expressed the substrate-specific subunit of system x c À , xCT, in HH514 BL cells. xCT-overexpressing cells became highly resistant to oxidative stress, particularly upon GSH depletion. Contrary to previous predictions, the increase of intracellular cysteine did not affect the cellular GSH pool, but concomitantly boosted extracellular cysteine concentrations. Even though cells were depleted of bulk GSH, xCT overexpression maintained cellular integrity by protecting against lipid peroxidation, a very early event in cell death progression. Our results show that system x c À protects against oxidative stress not by elevating intracellular GSH levels, but rather creates a reducing extracellular environment by driving a highly efficient cystine/cysteine redox cycle. Our findings show that the cystine/cysteine redox cycle by itself must be viewed as a discrete major regulator of cell survival.

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Section: Discussionmentioning

confidence: 99%

The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

et al. 2007

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“…Intracellular cystine is rapidly reduced to cysteine and incorporated into thiol containing proteins and GSH. xCT activity correlates with cellular GSH levels in a variety of cell types [37] and 3T3 cells that overexpress xCT were found to contain greater levels GSH than vector control cells ( Figure. 3A).…”

Section: Xct Overexpression Increases Intracellular Reduced Thiol Levmentioning

confidence: 99%

xCT expression reduces the early cell cycle requirement for calcium signaling

Lastro

Kourtidis

Farley

et al. 2008

Cellular Signalling

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Calcium has long been recognized as an important regulator of cell cycle transitions although the mechanisms are largely unknown. A functional genomic screen has identified genes involved in the regulation of early cell cycle progression by calcium. These genes when overexpressed confer the ability to bypass the G1/S arrest induced by Ca 2+ -channel antagonists in mouse fibroblasts. Overexpression of the cystine-glutamate exchanger, xCT, had the greatest ability to evade calcium antagonist-induced cell cycle arrest. xCT carries out the rate limiting step of glutathione synthesis in many cell types and is responsible for the uptake of cystine in most human cancer cell lines. Functional analysis indicates that the cystine uptake activity of xCT overcomes the G1/S arrest induced by Ca 2+ -channel antagonists by bypassing the requirement for calcium signaling. Since cells overexpressing xCT were found to have increased levels and activity of the AP-1 transcription factor in G1, redox stimulation of AP-1 activity accounts for the observed growth of these cells in the presence of calcium channel antagonists. These results suggest that reduced calcium signaling impairs AP-1 activation and that xCT expression may directly affect cell proliferation.

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“…The major antioxidant within cells is glutathione, a tripeptide that is synthesized from cysteine, glutamate, and glycine (18). Cystine is taken up by cells primarily through the xC(-) system, which is a heterodimeric protein consisting of a transporter subunit (xCT, encoded by the SLC7A11 gene) and a regulatory subunit (4F2hc, also known as CD98, encoded by the SLC3A2 gene) (19). In cells, cystine is reduced to cysteine and reacts with glutamate to form γ-glutamylcysteine in…”

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confidence: 99%

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Samanta

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

223

205

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Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogenactivated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.hypoxia-inducible factor | paclitaxel | pluripotency factors | chemotherapy resistance | tumor-initiating cells

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Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines

Cited by 166 publications

References 28 publications

The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

xCT expression reduces the early cell cycle requirement for calcium signaling

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

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