234 TARGETING STAT5 DEGRADES ANDROGEN RECEPTOR VIA THE PROTEASOME AND PROLONGS TIME TO TUMOR PROGRESSION POST CASTRATION IN VIVO
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Résumé
You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2010234 TARGETING STAT5 DEGRADES ANDROGEN RECEPTOR VIA THE PROTEASOME AND PROLONGS TIME TO TUMOR PROGRESSION POST CASTRATION IN VIVO Christian Thomas, Amina Zoubeidi, Hidetoshi Kuruma, Brett Monia, Youongsoo Kim, Robert MacLeod, and Martin E. Gleave Christian ThomasChristian Thomas Vancouver, Canada More articles by this author , Amina ZoubeidiAmina Zoubeidi Vancouver, Canada More articles by this author , Hidetoshi KurumaHidetoshi Kuruma Vancouver, Canada More articles by this author , Brett MoniaBrett Monia Carlsbad, CA More articles by this author , Youongsoo KimYouongsoo Kim Carlsbad, CA More articles by this author , Robert MacLeodRobert MacLeod Carlsbad, CA More articles by this author , and Martin E. GleaveMartin E. Gleave Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.292AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Signal transducer and activator of transcription 5 (STAT5) plays an important role in the transition of prostate cancer (PCa) to its hormone-refractory state. We hypothesize that pharmacological targeting of the active JAK2-STAT5 pathway may be a promising tool to delay clinical PCa progression, in part because STAT5 cooperates with androgen receptor (AR) to promote PCa progression. METHODS LNCaP, C4-2 and DU145 were transfected with control scramble (ScrB) or STAT5 antisense oligonucleotide (ASO) and submitted to westernblot, qRT-PCR and immunofluorescence analysis. LNCaP and C4-2 cells were transfected with STAT5 ASO or ScrB and tested for their ability to modulate PSA transactivation by luciferase assay. Cell viability was assessed by crystal violet and cell cycle by FACS analysis. AR stability was evaluated by cyclohexamide and MG132 treatment. Athymic male mice bearing LNCaP xenografts were castrated and randomly assigned to treatment with STAT5-ASO or control ScrB 12.5 mg/kg 3x weekly intraperitoneal. Tumor volume and serum prostate-specific antigen (PSA) were evaluated weekly. RESULTS STAT5 ASO potently inhibits STAT5 expression in LNCaP, C4-2 and DU145 at concentration as low as 30nM. Inhibition of STAT5 expression was accompanied by significantly decreased cell proliferation at 30nM (32.8-55.6%) and 50nM (60.3-70.6%) and significantly increased apoptotic rates at same concentrations (6.1-9.5% and 25.8-53.4%). Moreover, STAT5 knockdown abrogates androgen-induced AR nuclear translocation and PSA transactivation. Interestingly STAT5 knockdown decreases AR stability and induces AR degradation via the proteasome. Finally, targeting STAT5 in vivo delayed time to castrate resistant progression in LNCaP xenograft model. CONCLUSIONS This study reports, for the first time, preclinical proof-of-principle that STAT5 knockdown reduces AR levels and activity, and delays tumor progression of prostate cancer in vivo. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e91-e92 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christian Thomas Vancouver, Canada More articles by this author Amina Zoubeidi Vancouver, Canada More articles by this author Hidetoshi Kuruma Vancouver, Canada More articles by this author Brett Monia Carlsbad, CA More articles by this author Youongsoo Kim Carlsbad, CA More articles by this author Robert MacLeod Carlsbad, CA More articles by this author Martin E. Gleave Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,015 | 0,004 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».