title: Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells.
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.
authors.affiliation: Department of Radiation Oncology, University of Virginia Health Sciences Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: 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.
authors.forename: D L
authors.initials: DL
authors.lastname: Brautigan
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Parsons
authors.affiliation: Department of Radiation Oncology, University of Virginia Health Sciences Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Larner
mesh_terms: D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008297:Male; D011471:Prostatic Neoplasms; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C410798:AR protein, human; D020533:Angiogenesis Inhibitors; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C495901:TP53 protein, human; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex