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

doi:10.1016/j.isci.2022.104175

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

iScience. 2022 Mar 31;25(5):104175. doi: 10.1016/j.isci.2022.104175. eCollection 2022 May 20.

Authors

Nane C Kuznik¹, Valeria Solozobova¹, Irene I Lee^{2

3}, Nicole Jung⁴, Linxiao Yang⁵, Karin Nienhaus⁵, Emmanuel A Ntim¹, Jaice T Rottenberg^{2

3}, Claudia Muhle-Goll^{6

7}, Amrish Rajendra Kumar¹, Ravindra Peravali¹, Simone Gräßle⁴, Victor Gourain⁸, Célia Deville⁹, Laura Cato^{2

3}, Antje Neeb¹, Marco Dilger¹, Christina A Cramer von Clausbruch¹, Carsten Weiss¹, Bruno Kieffer⁹, G Ulrich Nienhaus^{1

5

10

11}, Myles Brown^{2

3}, Stefan Bräse^{4

7}, Andrew C B Cato¹

Affiliations

¹ Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
³ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Institute of Biological and Chemical Systems, Functional Molecular Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
⁵ Institute of Applied Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
⁶ Institute of Biological Interfaces 4, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
⁷ Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
⁸ LabEx IGO "Immunotherapy, Graft, Oncology", Centre de Recherche en Transplantation et Immunologie - UMR1064, 44093 Nantes, France.
⁹ 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.
¹⁰ Institute of Nanotechnology, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
¹¹ Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Abstract

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.

Keywords: Biochemical engineering; Cancer; Chemistry; Medical biochemistry.