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A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

Kuznik, Nane C. 1; Solozobova, Valeria 1; Lee, Irene I.; Jung, Nicole 2; Yang, Linxiao 3; Nienhaus, Karin 3; Ntim, Emmanuel A. 1; Rottenberg, Jaice T.; Muhle-Goll, Claudia ORCID iD icon 2,4; Kumar, Amrish Rajendra 1; Peravali, Ravindra 1; Gräßle, Simone 1; Gourain, Victor; Deville, Célia; Cato, Laura; Neeb, Antje 1; Dilger, Marco 1; Cramer von Clausbruch, Christina A. 1; Weiss, Carsten 5; ... mehr


BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer. Here, we show that BAG1L regulates AR dynamics in the nucleus and its ablation attenuates AR target gene expression especially those involved in oxidative stress and metabolism. We show that a small molecule, A4B17 that targets the BAG domain downregulates AR target genes similar to a complete BAG1L knockout and upregulates the expression of oxidative stress-induced genes involved in cell death. Furthermore, A4B17 outperformed the clinically approved antagonist enzalutamide in inhibiting cell proliferation and prostate tumor development in a mouse xenograft model. BAG1 inhibitors therefore offer unique opportunities for antagonizing AR action and prostate cancer growth.

Verlagsausgabe §
DOI: 10.5445/IR/1000144620
Veröffentlicht am 27.07.2022
DOI: 10.1016/j.isci.2022.104175
Zitationen: 1
Web of Science
Zitationen: 2
Zitationen: 3
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Angewandte Physik (APH)
Institut für Biologische Grenzflächen (IBG)
Institut für Biologische und Chemische Systeme (IBCS)
Institut für Nanotechnologie (INT)
Institut für Organische Chemie (IOC)
Publikationstyp Zeitschriftenaufsatz
Publikationsdatum 20.05.2022
Sprache Englisch
Identifikator ISSN: 2589-0042
KITopen-ID: 1000144620
HGF-Programm 47.14.02 (POF IV, LK 01) Information Storage and Processing in the Cell Nucleus
Weitere HGF-Programme 43.33.11 (POF IV, LK 01) Adaptive and Bioinstructive Materials Systems
Erschienen in iScience
Verlag Cell Press
Band 25
Heft 5
Seiten Art.Nr. 104175
Vorab online veröffentlicht am 31.03.2022
Nachgewiesen in Dimensions
Web of Science
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