Mechanistic insights into the regulation of pro-metastatic IL-1[beta] expression by androgen receptor in prostate cancer cells

Abstract

Prostate adenocarcinoma remains one of the most commonly diagnosed malignancies in men, and advanced disease continues to present major therapeutic challenges. The androgen receptor (AR) is the principal driver of prostate cancer progression, and inhibition of AR signaling remains the standard treatment for metastatic disease. However, many patients progress to metastatic castration-resistant prostate cancer (CRPC), a lethal stage characterized by heterogeneous tumor cell populations with distinct AR expression and activity states. We previously identified an inverse relationship between AR signaling and expression of interleukin-1[beta] (IL-1[beta]), a pro-inflammatory cytokine that promotes skeletal colonization and progression of prostate cancer cells. This dissertation investigated the molecular mechanisms governing IL-1[beta] regulation in prostate cancer and the role of tumor-derived IL-1[beta] in AR-heterogeneous tumors. We demonstrated that patients with low AR activity and high IL-1[beta] expression exhibit significantly worse overall survival than patients with high AR activity and low IL-1[beta] expression. Mechanistically, we found that AR splice variants, including AR-45 and AR-V7, repress IL-1[beta] transcription similarly to full-length AR. We further identified constitutive JAK2/STAT1 signaling as the pathway driving IL-1[beta] transcription specifically in AR-negative prostate cancer cells, while cathepsin B mediated IL-1[beta] maturation independently of canonical inflammasome activation and caspase-1 activity. Finally, we demonstrated that tumor-derived IL-1[beta] suppresses AR signaling and induces IL-1[beta] expression in neighboring AR-positive cells through paracrine signaling. Collectively, these findings establish a mechanistic framework linking AR signaling, JAK2/STAT1 activation, cathepsin B-dependent IL-1[beta] processing, and paracrine cytokine signaling in metastatic CRPC while identifying IL-1[beta] signaling as a potential therapeutic target in advanced prostate cancer.