Reversion of epithelial-mesenchymal transition by a novel agent DZ-50 via IGF binding protein-3 in prostate cancer cells
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Zheng Cao1, Shahriar Koochekpour2, Stephen E. Strup1 and Natasha Kyprianou1,3
1Department of Urology, University of Kentucky, Lexington, KY, USA
2Department of Genetics and Genomic and Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
3Departments of Biochemistry and Toxicology & Cancer Biology, University of Kentucky, Lexington, KY, USA
Natasha Kyprianou, email: [email protected]
Keywords: prostate stroma, targeted therapeutics, mesenchymal changes, tumor microenvironment, DZ-50
Received: February 23, 2017 Accepted: May 05, 2017 Published: July 28, 2017
Dysregulation of transforming growth factor-β1 (TGF-β1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin® derivative, DZ-50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT). This study demonstrates that DZ-50 increased expression of the epithelial marker E-cadherin, and decreased the mesenchymal marker N-cadherin in human prostate cancer cells. In DU-145 cells, the effect of DZ-50 on EMT towards mesenchymal epithelial transition (MET) was inhibited by talin1 overexpression, a focal adhesion regulator promoting anoikis resistance and tumor invasion. DZ-50 treatment of human prostate cancer cells and cancer-associated fibroblasts (CAFs) downregulated IGFBP3 expression at mRNA and protein level. In TGF-β1 responsive LNCaPTβRII, TGF-β1 reversed DZ-50-induced MET by antagonizing the drug-induced decrease of nuclear IGFBP3. Furthermore, co-culture with CAFs promoted prostate cancer epithelial cell invasion, an effect that was significantly inhibited by DZ-50. Our findings demonstrate that the lead compound, DZ-50, inhibited the invasive properties of prostate cancer epithelial cells by targeting IGFBP3 and mediating EMT conversion to MET. This study integrated the mechanisms underlying the effect of DZ-50 and further supported the therapeutic value of this compound in the treatment of advanced metastatic prostate cancer.
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