OR36-2 Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR36-Ovarian & Uterine Function
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 104 (Moscone Center)
So-Youn Kim*1, Marilia Cordeiro1, Vanida Serna2, Katy Ebbert3, Lindsey M Butler2, Satrajit Sinha4, Alea A. Mills5, Teresa K Woodruff1 and Takeshi Kurita1
1Northwestern University, Chicago, IL, 2Northwestern University, Chicago, 3Northwestern.edu, Chicago, 4Department of Biochemistry, Center for Excellence in Bioinformatics and Life Sciences, NY, 5Cold Spring Harbor Laboratories, Cold Spring Harbor NY, NY
Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy, especially platinum-based drugs. Early menopause and sterility are unintended consequences of chemotherapy and efforts to understand the oocyte damage/stress suicide 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 from cisplatin 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. Here, we report that prior to apoptosis, cisplatin induces nuclear-accumulation of c-Abl and TAp73 in the oocyte. Subsequently, oocytes undergoing apoptosis showed down-regulation of TAp63 and up-regulation of Bax. When mouse ovaries were treated with both cisplatin and imatinib, the c-Abl kinase inhibitor was unable to block cisplatin-induced DNA damage and damage-response, such as up-regulation of p53. However, imatinib specifically inhibited the nuclear accumulation of c-Abl and TAp73 and subsequent downregulation of TAp63 as well as upregulation of Bax, thus, abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63 in oocytes inhibited apoptosis as well as the accumulation of c-Abl and TAp73 caused by cisplatin. In contrast, the conditional deletion of DNp63 in the oocyte did not inhibit cisplatin-induced oocyte death.  Therefore, 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 propose that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would activate TAp73-Bax-mediated apoptosis.  As oocyte death acutely reduces the ovarian reserve, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt this progression and perhaps conserve the endocrine function of the ovary against the damaging effects of chemotherapy.

Nothing to Disclose: SYK, MC, VS, KE, LMB, SS, AAM, TKW, TK

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The Northwestern University Ovarian Histology Core: P01HD021921;RL1HD058295, UL1DE19587; R01CA154358 and R01HD064402