USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.
Open accessAbstract
Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Many small molecule USP7 inhibitors have been found to inhibit cancer cell growth in vitro and in animal xenograft models.
“While human trials of USP7 inhibitors have yet to be conducted, many of these compounds have been found to inhibit cancer cell growth in vitro, as well as in animal xenograft models (Fan et al., 2013; Agathanggelou et al., 2017; Turnbull et al., 2017; Peng et al., 2019; Zhang et al., 2020).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Fan et al., 2013
P22077 significantly enhances the efficacy of doxorubicin and etoposide to kill cultured neuroblastoma cells.
“For instance, P22077 has been found to significantly enhance the efficacy of the DNA damaging compounds doxorubicin and etoposide to kill cultured neuroblastoma cells (Fan et al., 2013).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Fan et al., 2013
Sensitization by P22077 in this study was dependent on a functional USP7-HDM2-p53 axis.
“While sensitization by P22077 was, in this study, found to be dependent on a functional USP7-HDM2-p53 axis, others have found USP7 inhibition may sensitize cancer cells to DNA damaging agents, even in p53 defective tumors.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Fan et al., 2013
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 43 · Cited by 199
- Authors
- Fan, Y.-H., Cheng, J., Vasudevan, S. A., Dou, J., Zhang, H., Patel, R. H., Ma, I. T., Rojas, Y., Zhao, Y., Yu, Y., Zhang, H., Shohet, J. M., Nuchtern, J. G., Kim, E. S., & Yang, J.
- Affiliations
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Yang, J
- Venue
- Cell Death & Disease
- Published
- 2013-10-17
- Volume
- 4
- Issue
- 10
- Pages
- e867-e867
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3920959
- OpenAlex
- W2001690964
- Cited by
- 199
- References
- 43
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 13 · 2023: 24 · 2022: 13 · 2021: 29 · 2020: 22 · 2019: 8 · 2018: 8 · 2017: 16 · 2016: 16 · 2015: 11 · 2014: 11
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- China Scholarship Council
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS072420)
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- neuroblastoma, USP7 inhibitors, USP7, p53 stabilization, p53-dependent apoptosis, chemosensitization, doxorubicin, etoposide, chemoresistance, childhood cancer
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Animals, Dose-Response Relationship, Drug, Doxorubicin, Humans, Neuroblastoma, Protease Inhibitors, Thiophenes, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Treatment Outcome, Apoptosis, Herpes Simplex Virus Protein Vmw65, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Ubiquitin Thiolesterase, Cell Line, Tumor, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
