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J. Pineal Res., Version of Record online: 18 JUL 2017, DOI: 10.1111/jpi.12432 Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles

Hoon Jang^1,†, Younghwa Na^2,†, Kwonho Hong^3,†, Sangho Lee¹, Sohyeon Moon¹, Minha Cho¹, Miseon Park⁴, Ok-Hee Lee¹, Eun Mi Chang⁴, Dong Ryul Lee¹, Jung Jae Ko^1,4, Woo Sik Lee⁴andYoungsok Choi^1,*

¹Department of Biomedical Science, CHA University, Gyeonggi, Korea
²College of Pharmacy, CHA University, Gyeonggi, Korea
³Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Korea
⁴Fertility Center of CHA Gangnam Medical Center, Department of Obstetrics and Gynecology, CHA University, Seoul, Korea

^†These authors contributed equally to this work.
^*Correspondence : Youngsok Choi, Department of Biomedical Science, CHA University, Gyeonggi, Korea.

Abstract

Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27Kip1, which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients.

Keywords : cisplatin;FOXO3a;ghrelin;melatonin;p27Kip1;premature ovarian failure;primordial follicle

논문정보

형식Research article
게재일2017년 07월 (BRIC 등록일 2017-07-21)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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