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.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer in men in the US [1,2].While localized PCa is not associated with a significant risk to mortality, a 5 year survival rate in those with metastatic disease is less than 30% [1]
RON Levels Are Significantly Elevated in Prostate Adenocarcinoma
We used immunohistochemistry to stain for RON in a set of tissue microarray consisting of radical prostatectomy specimens
Summary
Prostate cancer (PCa) is the second leading cause of cancer in men in the US [1,2]. While localized PCa is not associated with a significant risk to mortality, a 5 year survival rate in those with metastatic disease is less than 30% [1]. One of the drivers of distant metastasis is the progression of hormone-naïve or hormone-sensitive PCa towards a hormone-independent form known as castration-resistant prostate cancer (CRPC). The androgen receptor (AR) is the primary driver of PCa growth and expansion. Its ability to initiate downstream signaling through ligand-independent mechanisms, such as interactions with receptor tyrosine kinases (RTKs), leads to the onset of CRPC [3,4].
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