title: Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network.
abstract: Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not ΔNp63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy.
authors.affiliation: Division of Reproductive Biology and Clinical Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Kim
authors.forename: M H
authors.initials: MH
authors.lastname: Cordeiro
authors.forename: V A
authors.initials: VA
authors.lastname: Serna
authors.forename: K
authors.initials: K
authors.lastname: Ebbert
authors.forename: L M
authors.initials: LM
authors.lastname: Butler
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.forename: A A
authors.initials: AA
authors.lastname: Mills
authors.forename: T K
authors.initials: TK
authors.lastname: Woodruff
authors.forename: T
authors.initials: T
authors.lastname: Kurita
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009687:Nuclear Proteins / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D009866:Oogenesis / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010984:Platinum / Q000009:adverse effects* / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C454920:delta Np73, mouse; D010984:Platinum; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin