Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

Abstract

Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at 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) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt 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 in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA downregulates RORγ-stimulated AR expression and AR signaling, whereas digoxin upregulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol biosynthesis. Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.

Overview of Ursolic Acid Potential for the Treatment of Metabolic Disorders, Autoimmune Diseases, and Cancers via Nuclear Receptor Pathways

“…Concomitantly, UA disrupted RORγ-controlled apoptosis/cell cycle genes. In conclusion, UA elicits its antiproliferative effect against PCa and TNBC, in part, via targeting RORγ [117].…”

“…A recent interesting report by Zou et al emphasized the RORγ-dependent anti-proliferative role of UA against triple negative breast cancer (TNBC) cells, HCC70, and prostate cancer (PCa) cell lines C4-2B and 22Rv1 [117]. In the test cell lines, UA lowered RORγ activation, as shown by a luciferase reporter assay, in a dose-dependent manner.…”

Exploring the role of CDCA4 in liver hepatocellular carcinoma using bioinformatics analysis and experiments

“…Studies have suggested that Digoxin possesses anti-proliferative properties against prostate cancer and breast cancer cells. [ 50 ] Digoxin demonstrates potential therapeutic benefits for non-small cell lung cancer in humans by inhibiting the phosphorylation of a protein kinase implicated in tumor cell survival, proliferation, metastasis, and autophagy within the PI3K/Akt pathway signaling. Nevertheless, further proof is required to support these conclusions.…”