Abstract 4918: Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms

Abstract Natural compounds such as ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have also been at several clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) in tumor cells severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target in castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC). Previous studies implicated UA and digoxin as potential RORγ antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. UA also showed potent anti-growth effects in AR-positive prostate cancer cells compared to AR-negative prostate cancer cells. In TNBC cells, UA but not digoxin alters RORγ-regulated cell proliferation and apoptosis gene programs. Together, our study shows for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in prostate cancer and TNBC cells. Our finding that RORγ is a direct target of UA in specific type of cancer will help select patients with tumors that likely respond to UA treatment. Citation Format: Hongye Zou, Yatian Yang, Demin Cai, Hong-Wu Chen. Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4918.