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Oncogene. 2014 Jan 2;33(1):26-33. doi: 10.1038/onc.2012.561. Epub 2012 Dec 17.

Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells.

Author information

1
Department of Radiation Oncology, University of Virginia Health Sciences Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
2
1] Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA [2] Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
3
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Abstract

The androgen receptor (AR) has a vital role in the onset and progression of prostate cancer by promoting G1-S progression, possibly by functioning as a licensing factor for DNA replication. We here report that low dose 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, induces mitotic arrest in prostate cancer cells involving activation of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein) and degradation of the AR. Depletion of the AR by small interfering RNA (siRNA) eliminates 2-ME-induced arrest and introducing AR into PC3-M cells confers 2-ME-induced mitotic arrest. Knockdown of CHIP or MDM2 (mouse homolog of double minute 2 protein) individually or in combination reduced AR degradation and abrogated M phase arrest induced by 2-ME. Our data link AR degradation via ubiquitination to mitotic arrest. Targeting the AR by activating E3 ligases such as CHIP represents a novel strategy for the treatment of prostate cancer.

PMID:
23246967
PMCID:
PMC3899837
DOI:
10.1038/onc.2012.561
[Indexed for MEDLINE]
Free PMC Article

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