1. A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway
- Author
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Nane C. Kuznik, Valeria Solozobova, Irene I. Lee, Nicole Jung, Linxiao Yang, Karin Nienhaus, Emmanuel A. Ntim, Jaice T. Rottenberg, Claudia Muhle-Goll, Amrish Rajendra Kumar, Ravindra Peravali, Simone Gräßle, Victor Gourain, Célia Deville, Laura Cato, Antje Neeb, Marco Dilger, Christina A. Cramer von Clausbruch, Carsten Weiss, Bruno Kieffer, G. Ulrich Nienhaus, Myles Brown, Stefan Bräse, Andrew C.B. Cato, Karlsruhe Institute of Technology (KIT), Harvard Medical School [Boston] (HMS), Dana-Farber Cancer Institute [Boston], Team 6 : Impact of acute inflammation on host pathogen interactions and lung homeostasis (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, and KERANDEL-DION, Céline
- Subjects
Life sciences ,biology ,Biochemical engineering ,Chemistry ,Multidisciplinary ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,ddc:570 ,Medical biochemistry ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Cancer - Abstract
International audience; 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.
- Published
- 2022
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