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    Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model

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    Author
    McCarty, D.J.
    Huang, W.
    Kane, M.A.
    Date
    2017
    Journal
    Oncotarget
    Publisher
    Impact Journals LLC
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.18632/oncotarget.19762
    Abstract
    The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide. However, induction of apoptosis in these models is independent of the AR and its truncated variant, AR-V7, and instead likely results from sustained endoplasmic reticulum stress and deregulated calcium homeostasis. Using in silico molecular docking, we predict VNPT-178 and VNLG-74A bind the ATPase domain of BiP/Grp78 and Hsp70-1A with greater affinity than the AR. Disruption of 70 kDa heat shock protein function may be the underlying mechanism of action for these galeterone analogs. Therefore, despite simultaneously antagonizing AR activity, AR and/or AR-V7 expression alone may inadequately predict a patient's response to treatment with VNPT-178 or VNLG-74A. Future studies evaluating the context-specific limitations of these compounds may provide clarity for their clinical application. Copyright McCarty et al.
    Sponsors
    This work was supported in part by an NIH and NCI grant (R01CA129379), start-up funds from the University of Maryland School of Medicine and the Center for Biomolecular Therapeutics (CBT), Baltimore, MD 21201
    Keyword
    Apoptosis
    AR-V7
    CWR22Rv1
    Prostate cancer
    Unfolded protein response
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85031942512&doi=10.18632%2foncotarget.19762&partnerID=40&md5=c858b1fefff361d7d21b87ffd54b1cfa; http://hdl.handle.net/10713/10018
    ae974a485f413a2113503eed53cd6c53
    10.18632/oncotarget.19762
    Scopus Count
    Collections
    UMB Open Access Articles 2017

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