title: Targeting heat shock proteins in metastatic castration-resistant prostate cancer.
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.
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Azad
authors.affiliation: The Vancouver Prostate Centre, 2775 Laurel Street, 6th Floor, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: The Vancouver Prostate Centre, 2775 Laurel Street, 6th Floor, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006360:Heat-Shock Proteins; D011944:Receptors, Androgen