Reversion of epithelial-mesenchymal transition by a novel agent DZ-50 via IGF binding protein-3 in prostate cancer cells

Zheng Cao, Shahriar Koochekpour, Stephen E. Strup, Natasha Kyprianou

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 epithelialmesenchymal- 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.

Original languageEnglish
Pages (from-to)78507-78519
Number of pages13
JournalOncotarget
Volume8
Issue number45
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
The authors wish to thank Dr. Hong Pu and Dr. Patrick Hensley (Department of Urology, University of Kentucky, Lexington); Dr. Ching-Shih Chen, (Ohio State University, Columbus, OH and Academia Sinica, Taiwan); Dr. Sarah Martin for valuable discussions; and Lorie Howard for her assistance in the submission of the manuscript. The American Urological Association Urology Care Foundation Postdoctoral Research Scholarship (ZC), and the James F. Hardymon Endowment in Urologic Research at the University of Kentucky (NK).

Publisher Copyright:
© Cao et al.

Keywords

  • DZ-50
  • Mesenchymal changes
  • Prostate stroma
  • Targeted therapeutics
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology

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