Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer

• Main Authors: Izhar Singh Batth, Shih-Bo Huang, Michelle Villarreal, Jingjing Gong, Divya Chakravarthy, Brian Keppler, Sridharan Jayamohan, Pawel Osmulski, Jianping Xie, Paul Rivas, Roble Bedolla, Michael A. Liss, I-Tien Yeh, Robert Reddick, Hiroshi Miyamoto, Rita Ghosh, Addanki P Kumar
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: International Journal of Molecular Sciences
• Subjects: castration-resistant prostate cancer; receptor tyrosine kinase; RON; atomic force microscopy; 2-methoxyestradiol; epithelial mesenchymal transition
• Online Access: https://www.mdpi.com/1422-0067/22/4/1852
• ISSN: 1661-6596; 1422-0067

2-Methoxyestradiol (2-ME₂) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME₂ in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME₂ treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME₂ significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME₂ intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME₂ to target RON signaling may be a potential therapeutic modality for prostate cancer.