title: AR-v7 protein expression is regulated by protein kinase and phosphatase.
abstract: Failure of androgen-targeted therapy and progression of castration-resistant prostate cancer (CRPC) are often attributed to sustained expression of the androgen receptor (AR) and its major splice variant, AR-v7. Although the new generation of anti-androgens such as enzalutamide effectively inhibits AR activity, accumulating pre-clinical and clinical evidence indicates that AR-v7 remains constitutively active in driving CRPC progression. However, molecular mechanisms which control AR-v7 protein expression remain unclear. We apply multiple prostate cancer cell models to demonstrate that enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the gene context of cancer cells. The balance between PP-1 and Akt activation governs AR phosphorylation status and activation of the Mdm2 ubiquitin ligase. Mdm2 recognizes phosphorylated serine 213 of AR-v7, and induces AR-v7 ubiquitination and protein degradation. These findings highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked.
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Xie
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
mesh_terms: D017398:Alternative Splicing; D001549:Benzamides; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000737:chemistry; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D054875:Ubiquitination
chemical_list: C410798:AR protein, human; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; D012694:Serine; C540278:enzalutamide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D054645:Protein Phosphatase 1; D010744:Phosphoric Monoester Hydrolases; D046988:Proteasome Endopeptidase Complex
keywords: AR-v7; PP-1 and Akt; castration resistant prostate cancer; protein stability; serine phosphorylation