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

S Sarkar; D L Brautigan; S J Parsons; J M Larner

doi:10.1038/onc.2012.561

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

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

Authors

S Sarkar¹, D L Brautigan², S J Parsons³, J M Larner¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

2-Methoxyestradiol
Angiogenesis Inhibitors / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Estradiol / analogs & derivatives
Estradiol / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Humans
M Phase Cell Cycle Checkpoints
Male
Prostatic Neoplasms
Proteasome Endopeptidase Complex / metabolism
Proteolysis*
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA, Small Interfering / genetics
Receptors, Androgen / genetics
Receptors, Androgen / metabolism*
Tubulin Modulators / pharmacology
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Protein Ligases / physiology*

Substances

AR protein, human
Angiogenesis Inhibitors
RNA, Small Interfering
Receptors, Androgen
TP53 protein, human
Tubulin Modulators
Tumor Suppressor Protein p53
Estradiol
2-Methoxyestradiol
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
STUB1 protein, human
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding