Journal of experimental & clinical cancer research : CR · 2026
Prolyl-isomerase Pin1 drives platinum resistance by regulating Notch3 stability and function in ovarian cancer.
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Giuli Maria Valeria, Mancusi Angelica, Natiello Bianca, Di Cristofano Samuele, Reali Rebecca, Pignataro Maria Gemma, D'Andrea Daniel, Di Magno Laura, Nicoletti Carmine, Giorgi Alessandra, Macone Alberto, Camerini Serena, Casella Marialuisa, Peruzzi Giovanna, Zema Sabrina, Canettieri Gianluca, Tomao Federica, Palaia Innocenza, Pernazza Angelina, Rustighi Alessandra, Palermo Rocco, Raimondo Domenico, Monti Alessandra, Doti Nunzianna, d'Amati Giulia, Del Sal Giannino, Screpanti Isabella, Talora Claudio, Bellavia Diana, Checquolo Saula
Аннотация
BACKGROUND: Resistance to platinum-based drugs represents a major obstacle for the management of high-grade serous ovarian cancer (HGSOC) patients. Indeed, the selective pressure of platinum-based (PT) chemotherapy often leads to the outgrowth of platinum-resistant subclones. In this scenario, the underlying adaptive networks should be fully investigated to provide advances toward more streamlined and personalized care.
METHODS: We conducted a comprehensive analysis of Pin1/Notch3relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.We conducted a comprehensive analysis of relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.
RESULTS: Here, we demonstrated that carboplatin treatment of HGSOC cells promoted the activation of the Pin1/Notch3 axis, resulting in platinum resistance. Accordingly, HGSOC-bearing patients showing increased Pin1/Notch3 co-expression after PT-based chemotherapy correlated with a clinical worse response. Conversely, genetic targeting of Pin1 combined with carboplatin treatment sensitizes resistant cells to platinum-based therapy, both in vitro and in vivo, strongly reducing their Notch3-mediated metastatic potential in preclinical murine models. Mechanistically, Pin1-Notch3 binding favours protection of Notch3 from its GSK3β-mediated degradation, resulting in increased Notch3 expression.
CONCLUSIONS: Collectively, our findings identify the functional Pin1/Notch3 axis as an escape strategy from chemotherapy-induced cell death, thus suggesting a novel predictive role of the Pin1/Notch3 axis in the platinum response, which could be useful for implementing frontline treatments for HGSOC patients before recurrence.
METHODS: We conducted a comprehensive analysis of Pin1/Notch3relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.We conducted a comprehensive analysis of relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.
RESULTS: Here, we demonstrated that carboplatin treatment of HGSOC cells promoted the activation of the Pin1/Notch3 axis, resulting in platinum resistance. Accordingly, HGSOC-bearing patients showing increased Pin1/Notch3 co-expression after PT-based chemotherapy correlated with a clinical worse response. Conversely, genetic targeting of Pin1 combined with carboplatin treatment sensitizes resistant cells to platinum-based therapy, both in vitro and in vivo, strongly reducing their Notch3-mediated metastatic potential in preclinical murine models. Mechanistically, Pin1-Notch3 binding favours protection of Notch3 from its GSK3β-mediated degradation, resulting in increased Notch3 expression.
CONCLUSIONS: Collectively, our findings identify the functional Pin1/Notch3 axis as an escape strategy from chemotherapy-induced cell death, thus suggesting a novel predictive role of the Pin1/Notch3 axis in the platinum response, which could be useful for implementing frontline treatments for HGSOC patients before recurrence.
Предметные рубрики MeSH
HumansXenograft Model Antitumor AssaysFemaleAnimalsMiceOvarian NeoplasmsDrug Resistance, NeoplasmReceptor, Notch3NIMA-Interacting Peptidylprolyl IsomeraseNeoplasms, Cystic, Mucinous, and SerousCell Line, TumorCisplatinMolecular Dynamics SimulationMolecular Docking SimulationGlycogen Synthase Kinase 3 beta