title: Transcription factor Stat5 knockdown enhances androgen receptor degradation and delays castration-resistant prostate cancer progression in vivo.
abstract: Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumor-bearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-of-principle, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors.
authors.affiliation: The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, British Columbia, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kuruma
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Eliana
authors.initials: E
authors.lastname: Beraldi
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Thüroff
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen; D050799:STAT5 Transcription Factor; D046988:Proteasome Endopeptidase Complex