Abstract LB038: Identification of androgen receptor co-chaperone interactors implicated in castration resistant prostate cancer

Abstract Background: Prostate cancer (PCa) is the most common non-cutaneous cancer afflicting men, both in the United States and worldwide. Aberrant molecular signaling mechanisms mediated by the Androgen Receptor (AR) are attributed as the main culprits for the initiation and progression of PCa, and research efforts have focused on developing strategies to directly target the AR. In an alternative approach, molecular chaperones that are critical for the maturation and signaling of the AR have emerged as potential therapeutic targets. Our lab has demonstrated the potential of inhibitors that target AR cochaperones, FKBP51 and FKBP52, in PCa cells. Previously, FKBP51 and FKBP52 have been shown to play a role in cell proliferation and survival, steroid hormone receptor maturation, and other mechanisms highly implicated in prostate carcinogenesis. Therefore, it is imperative to understand the protein-protein interactions that regulate FKBP51 and FKBP52-mediated AR function in PCa. We hypothesize that unknown interactors cooperate with FKBP51 and FKBP52 to promote PCa progression via the AR signaling pathways. Here, we performed a series of experiments aimed to identify and characterize auxiliary proteins influencing FKBP51- and FKBP52-mediated AR activity. Ultimately, our goal is to define novel protein interactions involved in AR-mediated PCa progression for therapeutic intervention. Methods: We implemented tandem affinity purification followed by mass spectrometry analysis in 22RV1 PCa cells using FKBP51 and FKBP52 as bait. The spectral counts of proteins identified were then used to analyze protein-protein interactions through the IDEP workflow software. Gene Ontology (GO) term enrichment analysis was used to generate a STRING interaction network. Protein interactions of interest were then validated via reciprocal immunoprecipitations. Results: This interactome analysis resulted in 353 IDs for FKBP51 and FKBP52 interactors. Heatmaps representing top 100 interactors were generated for both bait proteins. Members of the peroxiredoxin family, implicated in development of PCa and resistance to treatment, are among the top candidates of interest resulting from this interactome. Conclusion: This analysis aims to provide important insights into the androgen signaling milieu, which can be applied in the development of novel treatments targeting AR interacting partners in PCa progression. This study contributes to the growing list of functionally diverse proteins that help modulate AR transcriptional activity, and supports the idea that AR signaling is dynamic with numerous molecules involved in the aberrant activation of AR in prostate-tumor cells Citation Format: Olga B. Soto, Abhijeet R. Patil, Sourav Roy, Marc B. Cox. Identification of androgen receptor co-chaperone interactors implicated in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB038.