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.
Written by:
Sarkar S, Brautigan DL, Parsons SJ, Larner JM. Are you the author?
Department of Radiation Oncology, University of Virginia Health Sciences Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
Reference: Oncogene. 2012 Dec 17(Epub ahead of print)
doi: 10.1038/onc.2012.561
PubMed Abstract
PMID: 23246967
