title: p53 protein aggregation promotes platinum resistance in ovarian cancer.
abstract: High-grade serous ovarian carcinoma (HGSOC), the most lethal gynecological cancer, often leads to chemoresistant diseases. The p53 protein is a key transcriptional factor regulating cellular homeostasis. A majority of HGSOCs have inactive p53 because of genetic mutations. However, genetic mutation is not the only cause of p53 inactivation. The aggregation of p53 protein has been discovered in different types of cancers and may be responsible for impairing the normal transcriptional activation and pro-apoptotic functions of p53. We demonstrated that in a unique population of HGSOC cancer cells with cancer stem cell properties, p53 protein aggregation is associated with p53 inactivation and platinum resistance. When these cancer stem cells differentiated into their chemosensitive progeny, they lost tumor-initiating capacity and p53 aggregates. In addition to the association of p53 aggregation and chemoresistance in HGSOC cells, we further demonstrated that the overexpression of a p53-positive regulator, p14ARF, inhibited MDM2-mediated p53 degradation and led to the imbalance of p53 turnover that promoted the formation of p53 aggregates. With in vitro and in vivo models, we demonstrated that the inhibition of p14ARF could suppress p53 aggregation and sensitize cancer cells to platinum treatment. Moreover, by two-dimensional gel electrophoresis and mass spectrometry we discovered that the aggregated p53 may function uniquely by interacting with proteins that are critical for cancer cell survival and tumor progression. Our findings help us understand the poor chemoresponse of a subset of HGSOC patients and suggest p53 aggregation as a new marker for chemoresistance. Our findings also suggest that inhibiting p53 aggregation can reactivate p53 pro-apoptotic function. Therefore, p53 aggregation is a potential therapeutic target for reversing chemoresistance. This is paramount for improving ovarian cancer patients' responses to chemotherapy, and thus increasing their survival rate.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang-Hartwich
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Soteras
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Z P
authors.initials: ZP
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sumi
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: V
authors.initials: V
authors.lastname: Craveiro
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: E
authors.initials: E
authors.lastname: Romanoff
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bingham
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: F
authors.initials: F
authors.lastname: Garofalo
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Alvero
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017671:Platinum Compounds / Q000627:therapeutic use*; D066329:Protein Aggregates / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; D066329:Protein Aggregates; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016190:Carboplatin