Key Points
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Heat shock proteins (HSPs) are molecular chaperones that regulate protein homeostasis, signal transduction and transcriptional networks, and are key drivers of adaptive stress-response pathways in many malignancies
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HSPs are highly expressed in many cancers, and subversion of their chaperone functions enables survival of malignant cells subjected to proteotoxic stress
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HSPs are important in androgen receptor function (including ligand binding and nuclear trafficking), and many HSP client proteins modulate key signalling and transductional networks in castration-resistant prostate cancer (CRPC) cells
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Extensive preclinical data have demonstrated the utility of targeting HSPs, including HSP90, HSP70, HSP27 and clusterin, in prostate cancer
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Clinical development of HSP blockade as a therapeutic strategy in CRPC has been challenging, but antisense oligonucleotides targeting HSP27 and clusterin have proceeded to late-stage clinical trials
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Integrating HSP blockade into the treatment paradigm for CRPC will require the development of potent, selective inhibitors of HSPs, and identification of rational combination strategies
Abstract
The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin–proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen–AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.
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A.A.A., A.Z. and K.N.C. researched data for the article. All authors made a substantial contribution to discussion of content. A.A.A. and A.Z. wrote the article. All authors contributed to review and editing of the manuscript before submission.
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A.A.A. declares honoraria from Janssen and receipt of research funding from Astellas. M.E.G. is listed as inventor on patent applications OGX 011 and OGX 427, submitted by the University of British Columbia, and licensed to OncoGenex Technologies, in which M.E.G. is a founding shareholder. K.N.C. declares receipt of research funding from Astellas, Janssen, Novartis and OncoGenex Technologies, and consultancy for Amgen, Astellas, Bayer, Janssen, Millennium, Novartis and Sanofi. A.Z. declares no competing interests.
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Azad, A., Zoubeidi, A., Gleave, M. et al. Targeting heat shock proteins in metastatic castration-resistant prostate cancer. Nat Rev Urol 12, 26–36 (2015). https://doi.org/10.1038/nrurol.2014.320
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DOI: https://doi.org/10.1038/nrurol.2014.320
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