Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4

Cancers

GianFranco Zannoni¹  Giovanni Scambia¹  Marsha Pellegrino²  Francesca Mancini²  Rossella Lucಠ Giorgia di Blasio²  Laura Fici²  Valentina Monteleone²  Germana Ciolli²  Marianna Buttarelli²  Fabiola Moretti²  Silvia Maiullari²  Alessandro Apollo²  Emanuela Teveroni²  Alessandra Ciucci³  Daniela Gallo³  Alfredo Pontecorvi⁴  Isabella Manni⁵  MariaPia Gentileschi⁶ 

[1] Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;Institute Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00015 Monterotondo, Italy;Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;Institute of Pathology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;SAFU unit, Department of Research, Diagnosis and Innovative Technologies, Traslational Research Area, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;

关键词: estrogen;    chemosensitivity;    MDM4;    sexual dimorphism;    intracellular trafficking;   

DOI  :  10.3390/cancers11091349

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown