Abstract 7307: Silibinin regulates glucocorticoid signaling via mast cells: Potential treatment of androgen-resistant prostate cancer

Abstract Prostate cancer (PCa) is the second most common cancer in American men. The American Cancer Society estimates that in 2023 there have been ~288,300 new cases of PCa and ~34,700 deaths from PCa in the United States. We previously showed that silibinin (SB; a natural flavonolignan from milk thistle seeds) is an effective therapeutic against PCa that inhibits cell growth and mitogenic cell survival via EGFR, IGFR-1, and NFκB signaling. However, the effect of SB on the tumor immunological microenvironment has not been elucidated. Mast cells (MCs) are archetypal solider of the immune system. The dynamics of PCa and MCs are complex, where they may contribute to tumor transformation/progression/regression; furthermore, their role in PCa is poorly understood. To address this gap and understand the role of SB in MC regulation, MCs were derived from the bone marrow (BMMCs) of C57BL/6 mice. BMMCs were generated in the presence of IL-3 and SCF, and were confirmed to be BMMCs using flow cytometry (dual staining: cKit/Fc€RI). Thereafter, the BMMCs were exposed to different doses of SB (25-100 µM) and two concentrations (25 µM; SB 25 and 100 µM; SB 100) were selected for further experiments. BMMCs treated with SB 25, SB 100, and untreated (control) were subjected to proteomic analysis using LCMS on Fusion Lumos mass spectrometer. A total of 3575 proteins were identified using the annotated mouse proteome. Statistical analysis was performed using ANOVA followed by Fisher’s posthoc analysis (p<0.05, FDR<0.01) and 166 proteins were found to be have statistically significant differential expression amongst the three groups (n=4/group). These 166 proteins were selected for further pathway analysis using Ingenuity Pathway Analysis (IPA; Qiagen). Only pathways specifically demonstrated experimentally in prostatic tissues/cells were selected for further analysis. Important nodes found for SB regulation of MCs in PCa were androgen receptor (AR), transmembrane serine protease (TMPRSS), and NK3 Homeobox 1 (NKX3-1). AR, TMPRSS, and NkX3-1 are well established in PCA. Most important pathway found was glucocorticoid receptor (GR) signaling; nuclear receptor subfamily 3 group C member 1 (NR3C1) and HS90 were the most important proteins identified in GR signaling. GR signaling may cause androgen deprivation therapy (ADT)-resistance by directly activating AR-target genes (including TMPRSS2) and/or activating an independent transcriptome. NR3C1 has been shown to share target specificity with AR and is highly upregulated in the resistant tumors. Thus, SB could play an important therapeutic role, specifically in ADT-resistant tumors via regulation of MCs. Further studies are warranted to delineate these mechanisms. Understanding these mechanistic could also potentially aid to decipher a general mechanism of resistance to antiandrogens and potential of SB in treating ADT-resistant tumors. Citation Format: Neha Mishra, Sandeep Paudel, Komal Raina, Paul Maroni, Chapla Agarwal, Rajesh Agarwal. Silibinin regulates glucocorticoid signaling via mast cells: Potential treatment of androgen-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7307.