Oncotarget

Research Papers:

Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer

Agnese Re, Claudia Colussi, Simona Nanni, Aurora Aiello, Lorenza Bacci, Claudio Grassi, Alfredo Pontecorvi and Antonella Farsetti _

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Oncotarget. 2018; 9:27985-27997. https://doi.org/10.18632/oncotarget.25462

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Abstract

Agnese Re1, Claudia Colussi1, Simona Nanni2, Aurora Aiello1,2, Lorenza Bacci2, Claudio Grassi3,4, Alfredo Pontecorvi2,4 and Antonella Farsetti1

1National Research Council (CNR), Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy

2Università Cattolica, Institute of Medical Pathology, Rome, Italy

3Università Cattolica, Institute of Human Physiology, Rome, Italy

4Fondazione Policlinico Universitario Gemelli, Rome, Italy

Correspondence to:

Antonella Farsetti, email: antonella.farsetti@cnr.it

Claudia Colussi, email: claudia.colussi@cnr.it

Alfredo Pontecorvi, email: alfredo.pontecorvi@unicatt.it

Keywords: prostate cancer; Nucleoporin 153; eNOS; Estrogen Receptor signaling; molecular biomarkers

Received: September 22, 2017    Accepted: May 07, 2018    Published: June 15, 2018

ABSTRACT

Nucleoporin 153 (Nup153), key regulator of nuclear import/export, has been recently associated to oncogenic properties in pancreatic and breast tumour cells modulating either cell motility and migration or gene expression by chromatin association.

In the present work, we have characterized the role of Nup153 in a cellular model of prostate cancer (PCa). The analysis of several immortalized cell lines derived from freshly explants of prostate cancer specimens showed that Nup153 protein was higher and present in multimeric complexes with eNOS and ERβ as compared to normal/hyperplastic prostate epithelial cells. This phenomenon was enhanced in the presence of 17β-estradiol (E2, 10-7M). Further experiments revealed that eNOS and ERβ were present in a DNA binding complexes associated with Nup153 promoter as demonstrated by ChIPs. Notably, after Nup153 depletion (siNup153), a reduction of migration capacity and colony formation in primary tumor-derived and metastatic PCa cells was observed. In addition, eNOS and ERβ nuclear localization was lost upon siNup 153 regardless of E2 treatment, suggesting that Nup153 is a key regulator of prostate cancer cell function and of the nuclear translocation of these proteins in response to hormone stimulus. Taken altogether our findings indicate that in PCa cells: i. the expression and function of Nup153 is modulated by estrogen signaling; ii. Nup153 contributes to cell migration and proliferation; iii. Nup153 regulates the nuclear translocation of eNOS and ERβ by forming a multimeric complex. Our findings unveil Nup153 as a novel component of the estrogen-dependent multimeric complex, thus representing a potential therapeutic candidate in prostate cancer.


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