iScience (May 2022)
A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway
- 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
Affiliations
- Nane C. Kuznik
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Valeria Solozobova
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Irene I. Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Nicole Jung
- Institute of Biological and Chemical Systems, Functional Molecular Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Linxiao Yang
- Institute of Applied Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
- Karin Nienhaus
- Institute of Applied Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
- Emmanuel A. Ntim
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Jaice T. Rottenberg
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Claudia Muhle-Goll
- Institute of Biological Interfaces 4, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
- Amrish Rajendra Kumar
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Ravindra Peravali
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Simone Gräßle
- Institute of Biological and Chemical Systems, Functional Molecular Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Victor Gourain
- LabEx IGO “Immunotherapy, Graft, Oncology”, Centre de Recherche en Transplantation et Immunologie - UMR1064, 44093 Nantes, France
- Célia Deville
- Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, U964, CNRS, UMR-7104, Université de Strasbourg, 67404 Illkirch-Graffenstaden, France
- Laura Cato
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Antje Neeb
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Marco Dilger
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Christina A. Cramer von Clausbruch
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Carsten Weiss
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany
- Bruno Kieffer
- Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, U964, CNRS, UMR-7104, Université de Strasbourg, 67404 Illkirch-Graffenstaden, France
- G. Ulrich Nienhaus
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; Institute of Applied Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany; Institute of Nanotechnology, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Stefan Bräse
- Institute of Biological and Chemical Systems, Functional Molecular Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany; Corresponding author
- Andrew C.B. Cato
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; Corresponding author
- Journal volume & issue
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Vol. 25,
no. 5
p. 104175
Abstract
Summary: 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.
