The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells
Open accessAbstract
TP53 is the most frequently mutated gene in human cancer and thus an attractive target for novel cancer therapy. Several compounds that can reactive mutant p53 protein have been identified. APR-246 is currently being tested in a phase II clinical trial in high-grade serous ovarian cancer. We have used RNA-seq analysis to study the effects of APR-246 on gene expression in human breast cancer cell lines. Although the effect of APR-246 on gene expression was largely cell line dependent, six genes were upregulated across all three cell lines studied, i.e., TRIM16, SLC7A11, TXNRD1, SRXN1, LOC344887, and SLC7A11-AS1. We did not detect upregulation of canonical p53 target genes such as CDKN1A (p21), 14-3-3σ, BBC3 (PUMA), and PMAIP1 (NOXA) by RNA-seq, but these genes were induced according to analysis by qPCR. Gene ontology analysis showed that APR-246 induced changes in pathways such as response to oxidative stress, gene expression, cell proliferation, response to nitrosative stress, and the glutathione biosynthesis process. Our results are consistent with the dual action of APR-246, i.e., reactivation of mutant p53 and modulation of redox activity. SLC7A11, TRIM16, TXNRD1, and SRXN1 are potential new pharmacodynamic biomarkers for assessing the response to APR-246 in both preclinical and clinical studies.
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Previous unbiased investigation of transcriptome changes in response to eprenetapopt treatment in cancer cells detected no changes to p53 target genes but up-regulation of oxidative stress response genes, including SLC7A11.
“previous unbiased investigation of the changes to the transcriptome in response to eprenetapopt treatment in cancer cells, which detected no changes to p53 target genes but up-regulation of oxidative stress response genes, including SLC7A11 (13, 35)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [13]
The Abstract and Discussion report that APR-246 upregulated SLC7A11 and other redox-associated genes in breast cancer cells. The Discussion says RNA-seq did not detect upregulation of several canonical p53 target genes, but qPCR found that those genes increased. Thus, “no changes to p53 target genes” is broader than the paper’s RNA-seq finding. (LLM, conf=0.88)
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Self-citation
- Authors
- Synnott, N. C., Madden, S. F., Bykov, V. J. N., Crown, J., Wiman, K. G., & Duffy, M. J.
- Affiliations
- University College Dublin (IE)
- Royal College of Surgeons in Ireland (IE)
- Karolinska Institutet (SE)
- St. Vincent's University Hospital (IE)
- Corresponding author
- Duffy, Michael J.
- ORCID
- Venue
- Translational Oncology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 11
- Issue
- 6
- Pages
- 1343-1349
- ISSN
- 1936-5233 (ISSN-L)
- PMC
- PMC6132178
- OpenAlex
- W2891832048
- Cited by
- 35
- References
- 44
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 5 · 2019: 2
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Oncology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT (CCRC13GAL)
- Cancer Clinical Research Trust
- Swedish Cancer Society (Cancerfonden
- Swedish Research Council (VR)
- Radiumhemmets Forskningsfonder
- ERC Advanced (TRANSREAD 694825)
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- APR-246, mutant p53, p53 reactivation, breast cancer, reactive oxygen species, oxidative stress, nitrosative stress, glutathione synthesis, SLC7A11, TRIM16, thioredoxin reductase 1, SRXN1, pharmacodynamic biomarkers, gene expression profiling, redox regulation
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