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Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impa...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770881/ https://www.ncbi.nlm.nih.gov/pubmed/31547268 http://dx.doi.org/10.3390/cancers11091349 |
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author | Lucà, Rossella di Blasio, Giorgia Gallo, Daniela Monteleone, Valentina Manni, Isabella Fici, Laura Buttarelli, Marianna Ciolli, Germana Pellegrino, Marsha Teveroni, Emanuela Maiullari, Silvia Ciucci, Alessandra Apollo, Alessandro Mancini, Francesca Gentileschi, Maria Pia Zannoni, Gian Franco Pontecorvi, Alfredo Scambia, Giovanni Moretti, Fabiola |
author_facet | Lucà, Rossella di Blasio, Giorgia Gallo, Daniela Monteleone, Valentina Manni, Isabella Fici, Laura Buttarelli, Marianna Ciolli, Germana Pellegrino, Marsha Teveroni, Emanuela Maiullari, Silvia Ciucci, Alessandra Apollo, Alessandro Mancini, Francesca Gentileschi, Maria Pia Zannoni, Gian Franco Pontecorvi, Alfredo Scambia, Giovanni Moretti, Fabiola |
author_sort | Lucà, Rossella |
collection | PubMed |
description | Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs. |
format | Online Article Text |
id | pubmed-6770881 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67708812019-10-30 Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 Lucà, Rossella di Blasio, Giorgia Gallo, Daniela Monteleone, Valentina Manni, Isabella Fici, Laura Buttarelli, Marianna Ciolli, Germana Pellegrino, Marsha Teveroni, Emanuela Maiullari, Silvia Ciucci, Alessandra Apollo, Alessandro Mancini, Francesca Gentileschi, Maria Pia Zannoni, Gian Franco Pontecorvi, Alfredo Scambia, Giovanni Moretti, Fabiola Cancers (Basel) Article Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs. MDPI 2019-09-12 /pmc/articles/PMC6770881/ /pubmed/31547268 http://dx.doi.org/10.3390/cancers11091349 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lucà, Rossella di Blasio, Giorgia Gallo, Daniela Monteleone, Valentina Manni, Isabella Fici, Laura Buttarelli, Marianna Ciolli, Germana Pellegrino, Marsha Teveroni, Emanuela Maiullari, Silvia Ciucci, Alessandra Apollo, Alessandro Mancini, Francesca Gentileschi, Maria Pia Zannoni, Gian Franco Pontecorvi, Alfredo Scambia, Giovanni Moretti, Fabiola Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title | Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title_full | Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title_fullStr | Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title_full_unstemmed | Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title_short | Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 |
title_sort | estrogens counteract platinum-chemosensitivity by modifying the subcellular localization of mdm4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770881/ https://www.ncbi.nlm.nih.gov/pubmed/31547268 http://dx.doi.org/10.3390/cancers11091349 |
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