Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors
Open accessAbstract
Strategies to induce p53 activation in wtp53-retaining tumors carry high potential in cancer therapy. Nutlin, a potent highly selective MDM2 inhibitor, induces non-genotoxic p53 activation. Although Nutlin shows promise in promoting cell death in hematopoietic malignancies, a major roadblock is that most solid cancers do not undergo apoptosis but merely reversible growth arrest. p53 inhibition by unopposed MDMX is one major cause for apoptosis resistance to Nutlin. The Hsp90 chaperone is ubiquitously activated in cancer cells and supports oncogenic survival pathways, many of which antagonize p53. The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) is known to induce p53-dependent apoptosis. We show here that in multiple difficult-to-kill solid tumor cells 17AAG modulates several critical components that synergize with Nutlin-activated p53 signaling to convert Nutlin's transient cytostatic response into a cytotoxic killing response in vitro and in xenografts. Combined with Nutlin, 17AAG destabilizes MDMX, reduces MDM2, induces PUMA and inhibits oncogenic survival pathways, such as PI3K/AKT, which counteract p53 signaling at multiple levels. Mechanistically, 17AAG interferes with the repressive MDMX-p53 axis by inducing robust MDMX degradation, thereby markedly increasing p53 transcription compared with Nutlin alone. To our knowledge Nutlin+17AAG represents the first effective pharmacologic knockdown of MDMX. Our study identifies 17AAG as a promising synthetic lethal partner for a more efficient Nutlin-based therapy.
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Co-treatment of cancer cells with 17-AAG to downregulate MDMX and nutlin 3a to antagonize the MDM2-p53 interaction yielded synergistic cytotoxic effects, probably owing to enhanced p53 activation.
“Co-treatment of such cancer cells with 17-AAG to downregulate MDMX, and nutlin 3a to antagonize the MDM2–p53 interaction, yielded synergistic cytotoxic effects, probably owing to enhanced p53 activation92.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [92]
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MDM2, MDMX and p53 in oncogenesis and cancer therapy
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- Authors
- Vaseva, A. V., Yallowitz, A. R., Marchenko, N. D., Xu, S., & Moll, U. M.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Moll, U M
- Venue
- Cell Death & Disease
- Published
- 2011-05-12
- Volume
- 2
- Issue
- 5
- Pages
- e156-e156
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3122118
- OpenAlex
- W2085740722
- Cited by
- 55
- References
- 40
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 4 · 2013: 11 · 2012: 8
- FWCI
- 3.62
- 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)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Deutsche Krebshilfe
- National Cancer Institute (CA0664, R01CA093853, CA93853)
- 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 › Cell death mechanisms and regulation
- Keywords
- 17-AAG, geldanamycin, HSP90 inhibition, nutlin, MDMX, MDM2, p53 activation, apoptosis, solid tumors, PI3K/Akt signaling, PUMA, synthetic lethality, combination therapy, tumor xenografts
- MeSH terms
- Animals, Drug Synergism, Enzyme Activation, Humans, Imidazoles, Male, Mice, Nude, Neoplasm Transplantation, Nuclear Proteins, Piperazines, Protein Binding, Proto-Oncogene Proteins, Transplantation, Heterologous, Tumor Suppressor Protein p53, Benzoquinones, Apoptosis, Cell Cycle Proteins, HSP90 Heat-Shock Proteins, Caspases, Cell Line, Tumor, Lactams, Macrocyclic, Tumor Burden, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Mice, Proto-Oncogene Proteins c-mdm2
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