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Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer

Rodriguez-Gonzalez, A. and Cyrus, K. and Salcius, M. and Kim, K. and Crews, C. M. and Deshaies, R. J. and Sakamoto, K. M. (2008) Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene, 27 (57). pp. 7201-7211. ISSN 0950-9232. PMCID PMC5573236. https://resolver.caltech.edu/CaltechAUTHORS:RODo08

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Abstract

Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1 alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ER alpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ER alpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ER alpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERa expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERa and AR, respectively.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/onc.2008.320DOIArticle
http://www.nature.com/onc/journal/v27/n57/abs/onc2008320a.htmlPublisherArticle
http://rdcu.be/c2ERPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573236/PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, R. J.0000-0002-3671-9354
Sakamoto, K. M.0000-0003-0494-8838
Additional Information:© 2008 Nature Publishing Group. Received 10 March 2008; revised 25 July 2008; accepted 27 July 2008; published online 15 September 2008. We thank Tammy Phung for her kind assistance in the flow cytometry performance in the UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Core Facility that is supported by the national Institutes of Health awards CA-16042 and AI-28697, by the Jonsson Cancer Center, the UCLA AIDS Institute and the David Geffen School of Medicine at UCLA. This work was supported by NIH R21 CA108545 (KMS), Department of Defense (USA) Prostate Cancer Research Program W81XWH-06-1-0192 (AR), Postdoctoral fellowship Ministerio de Educacion y Ciencia (Spain) MEC/Fulbright EX 2005-0517 (AR) and NIH R21 R21 CA118631 (CMC). RJD is an Investigator of the Howard Hughes Medical Institute.
Funders:
Funding AgencyGrant Number
NIHCA-16042
NIHAI-28697
Jonsson Cancer CenterUNSPECIFIED
UCLA AIDS InstituteUNSPECIFIED
David Geffen School of Medicine, UCLAUNSPECIFIED
NIHR21 CA108545
Department of DefenseW81XWH-06-1-0192
Ministerio de Educación y Ciencia (MEC)EX 2005-0517
Fulbright Scholar ProgramUNSPECIFIED
NIHR21 R21 CA118631
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:steroid hormone receptors; ubiquitination; degradation; breast cancer; prostate cancer
Issue or Number:57
PubMed Central ID:PMC5573236
Record Number:CaltechAUTHORS:RODo08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:RODo08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13292
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Feb 2009 20:37
Last Modified:03 Oct 2019 00:35

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