Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation
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TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system x C−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System x C− inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system x C− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.
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Inhibiting cystine uptake with erastin or sulfasalazine synergizes with eprenetapopt both in vitro and in vivo.
“This model is in keeping with our prior work, and confirmed by others (7, 8, 20), demonstrating that inhibiting cystine uptake with erastin or sulfasalazine synergizes with eprenetapopt both in vitro and in vivo.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
The Results section reports that both erastin and sulfasalazine (SAS) strongly synergized with APR-246 in cancer cells. In the in vivo xenograft experiments, it reports greater antitumour activity for SAS plus APR-246 than for either agent alone, but does not report an erastin combination in vivo. Thus the claim’s in vivo extension to both drugs is not supported by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMQ is a thiol-reactive Michael acceptor that forms reversible covalent bonds with thiol-containing molecules including cysteine and GSH.
“MQ is a thiol-reactive Michael acceptor that forms reversible covalent bonds with thiol-containing molecules including cysteine and the GSH (7, 8).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
The Results section reports that MQ reacts with GSH in cancer cells, and the Discussion says it forms a thioether. Our copy does not establish that MQ is a Michael acceptor, that its covalent bonds are reversible, or that it reacts with cysteine. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGSH depletion and/or factors that regulate GSH availability are central determinants of eprenetapopt activity in cancer cells, as opposed to p53 and associated apoptotic machinery.
“Our work supports previous findings reporting that GSH depletion and/or factors that regulate GSH availability are central determinants of eprenetapopt activity in cancer cells (6–8), as opposed to p53 and associated apoptotic machinery.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
The Discussion (page unavailable) calls GSH depletion integral to APR-246’s anti-tumour activity and identifies SLC7A11 expression and intracellular GSH as determinants of response. But it also says activity depends on mutant-p53 status, and describes cytochrome c release triggering apoptosis. Thus the source does not support setting GSH-related factors against p53 and apoptotic machinery as the claim does. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEprenetapopt induces lipid peroxidation following GSH depletion.
“In our prior work, we showed that eprenetapopt induces lipid peroxidation following GSH depletion (8).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
Exogenously supplied thiols block eprenetapopt activity in cancer cells.
“This is consistent with previous studies noting that exogenously supplied thiols block eprenetapopt activity in cancer cells (5, 8).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
Mutant p53 inhibits the activity of the antioxidant transcription factor Nrf2, which may lead to reduced expression of SLC7A11, a component of the xc cystine-glutamate antiporter, and thus decreased levels of GSH.
“Furthermore, mutant p53 has been shown to inhibit the activity of the antioxidant transcription factor Nrf2, which may lead to reduced expression of SLC7A11, a component of the xc cystine-glutamate antiporter, and thus decreased levels of GSH39.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [39]
Anticancer effects of eprenetapopt have been linked to GSH depletion and inhibition of the thioredoxin antioxidant system.
“As a result, the anticancer effects of eprenetapopt have been linked to GSH depletion and inhibition of the thioredoxin antioxidant system (7–9).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
Ferroptosis inhibitors failed to restore cell proliferation of eprenetapopt-treated cells.
“Ferroptosis inhibitors failed to restore cell proliferation of eprenetapopt-treated cells (as assessed by confluency), which likely explains our previous results using resazurin-based assays (Fig. 3, A and B) (8).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [8]
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- Authors
- Liu, D. S., Duong, C. P., Haupt, S., Montgomery, K. G., House, C. M., Azar, W. J., Pearson, H. B., Fisher, O. M., Read, M., Guerra, G. R., Haupt, Y., Cullinane, C., Wiman, K. G., Abrahmsen, L., Phillips, W. A., & Clemons, N. J.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Karolinska Institutet (SE)
- Corresponding author
- Phillips, Wayne A.
- Clemons, Nicholas J.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-03-28
- Volume
- 8
- Issue
- 1
- Pages
- 14844-14844
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5379068
- OpenAlex
- W2601818643
- Cited by
- 321
- References
- 46
- Citations by year
- 2026: 8 · 2025: 29 · 2024: 38 · 2023: 53 · 2022: 60 · 2021: 45 · 2020: 28 · 2019: 29 · 2018: 24 · 2017: 7
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation
- U.S. Department of Health and Human Services
- Victorian Cancer Agency (MCRF16002)
- Marshfield Clinic Research Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- University of Melbourne (MCRF16002)
- Peter MacCallum Cancer Centre
- State Government of Victoria
- Cancer Therapeutics Cooperative Research Centre
- Medical Research Council
- National Health and Medical Research Council (MCRF16002, 1040947, 1120293)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- mutant p53, system xc-, SLC7A11, glutathione synthesis, Nrf2, APR-246, oxidative stress, lipid peroxidation, apoptosis, predictive biomarkers, combination therapy, cancer therapy
- MeSH terms
- Glutathione, Humans, Models, Biological, Mutation, Quinuclidines, Stress, Physiological, Lipid Peroxidation, Tumor Suppressor Protein p53, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Amino Acid Transport System y+, Cell Line, Tumor, NF-E2-Related Factor 2
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