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Synergistic effect of melatonin and ghrelin in preventing cisplatin‐induced ovarian damage via regulation of FOXO 3a phosphorylation and binding to the p27 Kip1 promoter in primordial follicles
Author(s) -
Jang Hoon,
Na Younghwa,
Hong Kwonho,
Lee Sangho,
Moon Sohyeon,
Cho Minha,
Park Miseon,
Lee OkHee,
Chang Eun Mi,
Lee Dong Ryul,
Ko Jung Jae,
Lee Woo Sik,
Choi Youngsok
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12432
Subject(s) - melatonin , ghrelin , endocrinology , medicine , cisplatin , biology , ovary , hormone , chemotherapy
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 FOXO 3a that induces cytoplasmic translocation of FOXO 3a. Inhibition of FOXO 3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO 3a for the p27 Kip1 promoter in primordial follicles. Co‐administration of melatonin and ghrelin in cisplatin‐treated ovaries restored the expression of p27 Kip1 , 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.