Zou Hongye, Yang Yatian, Chen Hong-Wu
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United States.
UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States.
Front Pharmacol. 2023 Apr 26;14:1146741. doi: 10.3389/fphar.2023.1146741. eCollection 2023.
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.
从水果和其他植物中分离出的天然化合物熊果酸（UA）和地高辛在临床前研究中显示出强大的抗癌作用。UA和地高辛已进入包括前列腺癌、胰腺癌和乳腺癌在内的不同癌症的治疗临床试验。然而，它们对患者的益处有限。目前，对其直接靶点和作用机制（MOA）的了解不足严重阻碍了它们的进一步开发。我们之前将核受体RORγ鉴定为去势抵抗性前列腺癌（CRPC）和三阴性乳腺癌（TNBC）的新型治疗靶点，并证明肿瘤细胞RORγ直接激活雄激素受体（AR）信号传导和胆固醇代谢等基因程序。先前的研究还表明，UA和地高辛在调节免疫细胞（如Th17细胞）功能方面是潜在的RORγt拮抗剂。在此我们表明，UA在抑制癌细胞中RORγ依赖性反式激活功能方面具有强大活性，而地高辛在临床相关浓度下无此作用。在前列腺癌细胞中，UA下调RORγ刺激的AR表达和AR信号传导，而地高辛上调AR信号通路。在TNBC细胞中，UA而非地高辛改变RORγ控制的细胞增殖、凋亡和胆固醇生物合成的基因程序。总之，我们的研究首次揭示UA而非地高辛在癌细胞中作为RORγ的天然拮抗剂发挥作用。我们发现RORγ是癌细胞中UA的直接靶点，这将有助于选择可能对UA治疗有反应的肿瘤患者。
