Abstract
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.
Highlights
Prostate cancer accounts for 21% of cancer diagnoses and 8% of cancer-related deaths in men with a total of 180,890 new cases and 26,120 deaths estimated in 2016 in the United States [1]
DZ-50-induction of E-cadherin mRNA and downregulation of N-cadherin, slug and snail mRNA were prevented by elevated talin1 (Figure 1B)
Phenotypic EMT profiling in DU-145 and DU-145talin1 cells revealed that DZ-50 (2μM; 48hrs) decreased IGF binding protein-3 (IGFBP3), N-cadherin, zinc finger E-box-binding protein1 (ZEB1) and vimentin protein expression (Figure 1C)
Summary
Prostate cancer accounts for 21% of cancer diagnoses and 8% of cancer-related deaths in men with a total of 180,890 new cases and 26,120 deaths estimated in 2016 in the United States [1]. Taxanes, including docetaxel and cabazitaxel, are 1st and 2nd line chemotherapy respectively, for the treatment of patients with mCRPC developing resistance to ADT [7], and contribute to only a modest improvement of survival [8,9,10]. Overriding this resistance requires understanding www.impactjournals.com/oncotarget of the driving mechanisms, besides the AR in CRPC in the context of the tumor microenvironment and development of targeted therapeutics
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
