Evidence for 2-methoxyestradiol-mediated inhibition of receptor tyrosine kinase ron in the management of prostate cancer

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number1852
Pages (from-to)1-18
Number of pages18
JournalInternational journal of molecular sciences
Volume22
Issue number4
DOIs
StatePublished - Feb 2 2021

Keywords

  • 2-methoxyestradiol
  • Atomic force microscopy
  • Bile acids
  • Castration-resistant prostate cancer
  • Epithelial mesenchymal transition
  • Mechanical properties
  • Prostate cancer disparities
  • RON
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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