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

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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