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    Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer

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    Name:
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    Description:
    Final Accepted Manuscript
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    Author
    Nollet, Eric A
    Cardo-Vila, Marina
    Ganguly, Sourik S
    Tran, Jack D
    Schulz, Veronique V
    Cress, Anne
    Corey, Eva
    Miranti, Cindy K
    Affiliation
    Univ Arizona, Ctr Canc, Dept Cellular & Mol Med
    Issue Date
    2020-06-21
    
    Metadata
    Show full item record
    Publisher
    NATURE PUBLISHING GROUP
    Citation
    Nollet, E.A., Cardo-Vila, M., Ganguly, S.S. et al. Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer. Oncogene (2020).
    Journal
    ONCOGENE
    Rights
    Copyright © The Author(s), under exclusive licence to Springer Nature Limited 2020.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    The androgen receptor (AR) is the major driver of prostate cancer growth and survival. However, almost all patients relapse with castration-resistant disease (CRPC) when treated with anti-androgen therapy. In CRPC, AR is often aberrantly activated independent of androgen. Targeting survival pathways downstream of AR could be a viable strategy to overcome CRPC. Surprisingly, little is known about how AR drives prostate cancer survival. Furthermore, CRPC tumors in which Pten is lost are also resistant to eradication by PI3K inhibitors. We sought to identify the mechanism by which AR drives tumor survival in CRPC to identify ways to overcome resistance to PI3K inhibition. We found that integrins alpha 6 beta 1 and Bnip3 are selectively elevated in CRPC downstream of AR. While integrin alpha 6 promotes survival and is a direct transcriptional target of AR, the ability of AR to induce Bnip3 is dependent on adhesion to laminin and integrin alpha 6 beta 1-dependent nuclear translocation of HIF1 alpha. Integrins alpha 6 beta 1 and Bnip3 were found to promote survival of CRPC cells selectively on laminin through the induction of autophagy and mitophagy. Furthermore, blocking Bnip3 or integrin alpha 6 beta 1 restored sensitivity to PI3K inhibitors in Pten-negative CRPC. We identified an AR driven pathway that cooperates with laminin and hypoxia to drive resistance to PI3K inhibitors. These findings can help explain in part why PI3K inhibitors have failed in clinical trials to overcome AR-dependent CRPC.
    Note
    6 month embargo; published online: 21 June 2020
    ISSN
    0950-9232
    PubMed ID
    32565538
    DOI
    10.1038/s41388-020-1370-9
    Version
    Final accepted manuscript
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41388-020-1370-9
    Scopus Count
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    UA Faculty Publications

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