Evidence map›Paper›PMID 25827424›Full record

ArticleRedox biology2015

Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress.

Eric Habib, Katja Linher-Melville, Han-Xin Lin, Gurmit Singh

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Redox biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 168 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
168citing papers in PubMed, 1 pooled it
5.1field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

168 citing papers in PubMed, 1 synthesis or guideline pooled it, 261 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Significance of GSH and HRedox report : communications in free radical research · 2026
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  10. Silver Tip (International journal of molecular sciences · 2026
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108 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 1 institution in 1 country.

Eric HabibDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8S 4L8.
Katja Linher-MelvilleDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8S 4L8.
Han-Xin LinDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8S 4L8.
Gurmit SinghDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8S 4L8. Electronic address: singhg@mcmaster.ca.
McMaster University · CA

Funding

Canadian Institutes of Health Research
6 · The paper itself

Abstract

Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate by activating key transcription factors. One such master regulator, the redox sensitive transcription factor NF E2 Related Factor 2 (NRF2), controls the expression of cellular defense genes including those encoding intracellular redox-balancing proteins involved in glutathione (GSH) synthesis. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) targets NRF2 for ubiquitination. In response to oxidative stress, NRF2 dissociates from KEAP1, entering the nucleus and binding to the antioxidant response element (ARE) in the promoter of its target genes. Elevated reactive oxygen species (ROS) production may deplete GSH levels within cancer cells. System xc(-), an antiporter that exports glutamate while importing cystine to be converted into cysteine for GSH synthesis, is upregulated in cancer cells in response to oxidative stress. Here, we provided evidence that the expression of xCT, the light chain subunit of system xc(-), is regulated by NRF2 in representative human breast cancer cells. Hydrogen peroxide (H2O2) treatment increased nuclear translocation of NRF2, also increasing levels of xCT mRNA and protein and extracellular glutamate release. Overexpression of NRF2 up-regulated the activity of the xCT promoter, which contains a proximal ARE. In contrast, overexpression of KEAP1 repressed promoter activity and decreased xCT protein levels, while siRNA knockdown of KEAP1 up-regulated xCT protein levels and transporter activity. These results demonstrate the importance of the KEAP1/NRF2 pathway in balancing oxidative stress in breast cancer cells through system xc(-). We have previously shown that xCT is upregulated in various cancer cell lines under oxidative stress. In the current investigation, we focused on MCF-7 cells as a model for mechanistic studies.

Indexed as

Oxidative StressAmino Acid Transport System y+Breast NeoplasmsCell NucleusFemaleGene Expression Regulation, NeoplasticGlutamic AcidGlutathioneHumansHydrogen PeroxideIntracellular Signaling Peptides and ProteinsKelch-Like ECH-Associated Protein 1MCF-7 CellsNF-E2-Related Factor 2Promoter Regions, GeneticProtein SubunitsAmino Acid Transport System y+Glutamic AcidGlutathioneHydrogen PeroxideIntracellular Signaling Peptides and ProteinsKEAP1 protein, humanKelch-Like ECH-Associated Protein 1NF-E2-Related Factor 2Protein SubunitsReactive Oxygen SpeciesRNA, Small InterferingSLC7A11 protein, humanHydrogen peroxideKEAP1NRF2Oxidative stressSystem x(c)(−)xCT

Identifiers

PMID25827424
PMCPMC4392061
OpenAlexW2015360869

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.