A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway
Nane C Kuznik, Valeria Solozobova, Irene Lee, Nicole Jung, Linxiao Yang, Karin Nienhaus, Emmanuel Amankwah Ntim, Jaice T. Rottenberg, Claudia Muhle‐Goll, Amrish 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
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.