Therapeutic Efficacy of p53 Restoration in Mdm2 -Overexpressing Tumors
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Abstract
UNLABELLED: The p53 (TP53) tumor suppressor is the most frequently mutated gene in human cancers. Restoring expression of wild-type p53 has led to tumor growth suppression in a variety of tumor models that are p53 deficient. Other mechanisms, for example, upregulation of Mdm2, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, the effects of restoring p53 activity were probed in Mdm2-overexpressing tumors genetically using animal models. Here, it was demonstrated that elevated levels of Mdm2 and decreased levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development. Our data further indicate that restoration of wild-type p53 expression in Mdm2-overexpressing angiosarcomas results in tumor stasis and regression in some cases. Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the Mdm2-overexpressing angiosarcomas. IMPLICATIONS: Restoration of wild-type p53 expression in Mdm2-overexpressing tumors suppresses tumor growth, which represents a potential clinical strategy to treat tumors with high levels of Mdm2.
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In addition to activating p53, Nutlin stabilizes Mdm2, raising Mdm2 levels that dampen the p53 response to DNA damage and increase sensitivity to genotoxic drugs.
“Our data suggest that in addition to p53 activation, Nutlin is also stabilizing Mdm2 causing an increase in the levels of Mdm2, which dampens the p53 response to DNA damage, resulting in increased sensitivity to genotoxic drugs (22,23).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [22]
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- Authors
- Li, Q., Zhang, Y., El-Naggar, A. K., Xiong, S., Yang, P., Jackson, J. G., Chau, G., & Lozano, G.
- Affiliations
- Authors' Affiliations: 1Department of Genetics,
- 3Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
- Corresponding author
- Lozano, Guillermina
- Venue
- Molecular Cancer Research
- Published
- 2014-06-01
- Volume
- 12
- Issue
- 6
- Pages
- 901-911
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC4058386
- OpenAlex
- W2144615015
- Cited by
- 30
- References
- 37
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 1 · 2016: 5 · 2015: 3 · 2014: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA47296, R01CA047296, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- p53 restoration, MDM2 overexpression, angiosarcoma, DNA damage response, tumor growth inhibition, E3 ubiquitin ligase, tumor regression, cell proliferation, apoptosis
- MeSH terms
- Animals, Female, Hemangiosarcoma, Immunohistochemistry, Male, Mice, Inbred C57BL, Mice, Transgenic, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Genes, p53, Tumor Suppressor Protein p53, Apoptosis, Cell Line, Tumor, Cell Growth Processes, Mice, Proto-Oncogene Proteins c-mdm2
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