Dual Targeting of HSC70 and HSP72 Inhibits HSP90 Function and Induces Tumor-Specific Apoptosis
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Heat-shock protein 70 (HSP70) isoforms contribute to tumorigenesis through their well-documented antiapoptotic activity and via their role as cochaperones for the HSP90 molecular chaperone. HSP70 expression is induced following treatment with HSP90 inhibitors, which may attenuate the cell death effects of this class of inhibitor. Here we show that silencing either heat-shock cognate 70 (HSC70) or HSP72 expression in human cancer cell lines has no effect on HSP90 activity or cell proliferation. However, simultaneously reducing the expression of both of these isoforms induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis. Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window.
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Hsp70 may promote tumor resistance to therapy.
“the latter of which may promote tumor resistance to therapy (23, 25)”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [23]
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- Authors
- Powers, M. V., Clarke, P. A., & Workman, P.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Workman, Paul
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 14
- Issue
- 3
- Pages
- 250-262
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2170573493
- Cited by
- 307
- References
- 36
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 15 · 2020: 8 · 2019: 17 · 2018: 16 · 2017: 18 · 2016: 24 · 2015: 25 · 2014: 27 · 2013: 29 · 2012: 24
- FWCI
- 10.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK (C309/A8274, C309/A2187)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Hsc70, HSP72, HSP90, Hsp90 inhibitors, proteasomal degradation, Hsp90 client proteins, G1 cell cycle arrest, heat shock proteins, cancer cell lines, therapeutic window, anti-apoptotic effects
- MeSH terms
- Bortezomib, Boronic Acids, Cell Cycle, Cell Line, Humans, Kinetics, Neoplasms, Poly(ADP-ribose) Polymerases, Protease Inhibitors, Pyrazines, Transfection, Benzoquinones, Apoptosis, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Proto-Oncogene Proteins c-raf, Protein Isoforms, RNA, Small Interfering, HCT116 Cells, Cell Line, Tumor, Proteasome Endopeptidase Complex, Lactams, Macrocyclic, Cell Proliferation, HSC70 Heat-Shock Proteins, HSP72 Heat-Shock Proteins, Cyclin-Dependent Kinase 4, Ubiquitination, Proteasome Inhibitors
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