title: Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary.
abstract: Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients.
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Youngeun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Miseon
authors.initials: M
authors.lastname: Park
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Functional Genomics, School of Engineering, University of Science and Technology (UST), Daejeon, Korea.
authors.forename: Jeong-Woong
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan-si, Chungcheongnam-do, Korea.
authors.forename: Kwonho
authors.initials: K
authors.lastname: Hong
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Jung Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Nam Keun
authors.initials: NK
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Ko
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.|Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, 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, Korea.
authors.forename: Tae Ki
authors.initials: TK
authors.lastname: Yoon
authors.affiliation: Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Korea.|Department of Obstetrics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Youngsok
authors.identifier: http://orcid.org/0000-0002-3862-4105
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D006080:Ovarian Follicle / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D008550:Melatonin; D002945:Cisplatin
keywords: FOXO3a; cisplatin; melatonin; premature ovarian failure; primordial follicle