title: Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice.
abstract: Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH) receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation.
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Chang
authors.affiliation: Department of Biomedical Science, CHA University, Sungnam-Si, Republic of Korea.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.|Department of Biomedical Science, CHA University, Sungnam-Si, Republic of Korea.
authors.forename: Sookyoung
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Kyungah
authors.initials: K
authors.lastname: Jeong
authors.affiliation: Department of Biomedical Science, CHA University, Sungnam-Si, Republic of Korea.
authors.forename: Sijeong
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.|Department of Biomedical Science, CHA University, Sungnam-Si, Republic of Korea.
authors.forename: Dong Ryul
authors.initials: DR
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.
authors.forename: Tae Ki
authors.initials: TK
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Science, CHA University, Sungnam-Si, Republic of Korea.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D005306:Fertilization / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009865:Oocytes / Q000502:physiology; D006080:Ovarian Follicle / Q000187:drug effects / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D065851:Ovarian Reserve / Q000187:drug effects*; D010060:Ovulation / Q000187:drug effects / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011974:Receptors, LH / Q000096:biosynthesis
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D011974:Receptors, LH; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D002945:Cisplatin