Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice

• Published in: PloS one 2015-12, Vol.10 (12), p.e0144245
• Main Authors: Chang, Eun Mi, Lim, Eunjin, Yoon, Sookyoung, Jeong, Kyungah, Bae, Sijeong, Lee, Dong Ryul, Yoon, Tae Ki, Choi, Youngsok, Lee, Woo Sik
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - physiology; Cancer; Cancer therapies; Cell cycle; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA adducts; Drug dosages; Drug resistance; Failure; Female; Fertilization; Fertilization - physiology; Follicles; Forkhead Box Protein O3; Forkhead Transcription Factors - metabolism; FOXO3 protein; Gynecology; Kinases; Laboratory animals; Luteinizing hormone; Maturation; Mice; Mice, Inbred ICR; Obstetrics; Oocytes; Oocytes - physiology; Ovarian cancer; Ovarian carcinoma; Ovarian Follicle - drug effects; Ovarian Follicle - physiology; Ovarian Neoplasms - drug therapy; Ovarian Reserve - drug effects; Ovulation; Ovulation - drug effects; Ovulation - physiology; Phosphorylation; Primary Ovarian Insufficiency - chemically induced; Primary Ovarian Insufficiency - pathology; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptors, LH - biosynthesis; Reproductive status; Rodents; Science; Side effects; Signal transduction; Toxicity; Transcription factors; Translocation; Tumor suppressor genes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0144245

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.