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

doi:10.18632/oncotarget.19659

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

Urology

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	78507-78519
Number of pages	13
Journal	Oncotarget
Volume	8
Issue number	45
DOIs	https://doi.org/10.18632/oncotarget.19659
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.19659

Cite this

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

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{\textregistered} 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.",

keywords = "DZ-50, Mesenchymal changes, Prostate stroma, Targeted therapeutics, Tumor microenvironment",

author = "Zheng Cao and Shahriar Koochekpour and Strup, {Stephen E.} and Natasha Kyprianou",

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: {\textcopyright} Cao et al.",

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AU - Kyprianou, Natasha

N1 - 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.

PY - 2017

Y1 - 2017

N2 - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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