Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer
AuthorNollet, Eric A
Ganguly, Sourik S
Tran, Jack D
Schulz, Veronique V
Miranti, Cindy K
AffiliationUniv Arizona, Ctr Canc, Dept Cellular & Mol Med
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationNollet, 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).
RightsCopyright © The Author(s), under exclusive licence to Springer Nature Limited 2020.
Collection InformationThis 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 email@example.com.
AbstractThe 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.
Note6 month embargo; published online: 21 June 2020
VersionFinal accepted manuscript
- The androgen receptor induces integrin α6β1 to promote prostate tumor cell survival via NF-κB and Bcl-xL Independently of PI3K signaling.
- Authors: Lamb LE, Zarif JC, Miranti CK
- Issue date: 2011 Apr 1
- Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.
- Authors: Toth RK, Tran JD, Muldong MT, Nollet EA, Schulz VV, Jensen CC, Hazlehurst LA, Corey E, Durden D, Jamieson C, Miranti CK, Warfel NA
- Issue date: 2019
- Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.
- Authors: Chattopadhyay I, Wang J, Qin M, Gao L, Holtz R, Vessella RL, Leach RW, Gelman IH
- Issue date: 2017 Feb 7
- NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer.
- Authors: Yu C, Wu G, Li R, Gao L, Yang F, Zhao Y, Zhang J, Zhang R, Zhang J, Yao L, Yuan J, Li X
- Issue date: 2015
- Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.
- Authors: McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, Fedele CG, Brown S, Dyson JM, Cottle DL, Cowling BS, Niranjan B, Risbridger GP, Mitchell CA
- Issue date: 2013 Aug 15