Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice.
Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice.
复制标题
顺铂通过PTEN/AKT/FOXO3A途径诱导休眠原始卵泡过度活化，从而导致小鼠卵巢储备的损失。
DOI：
10.1371/journal.pone.0144245
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lee WS
中科院分区：
文献类型：
--
作者：
Chang EM;Lim E;Yoon S;Jeong K;Bae S;Lee DR;Yoon TK;Choi Y;Lee WS
顺铂是卵巢癌的一线化疗药物，其作用是促进DNA交联和加合。然而，耐药性和相当大的副作用，包括生殖毒性，仍然是一个重大的挑战。PTEN是一种肿瘤抑制因子，在细胞周期调控、细胞凋亡和肿瘤发生发展中起重要作用。与此同时，已发现PTEN对于原始卵泡池的维持至关重要。在本研究中，我们研究了PTEN/Akt/FOXO 3通路在顺铂诱导的原始卵泡耗竭中的作用。使用顺铂诱导的卵巢衰竭小鼠模型来评估该途径如何参与。体外成熟用于顺铂损伤后的卵母细胞拯救。我们发现顺铂治疗降低了PTEN水平，导致随后该途径中关键分子磷酸化的增加。PTEN/Akt/FOXO 3通路级联的激活增加了顺铂处理的卵泡中FOXO 3a的胞质易位，这反过来增加了生长卵泡的池大小，并迅速耗尽休眠卵泡的数量。一旦激活，卵泡更容易凋亡，其卵丘细胞显示出黄体生成素（LH）受体表达的丧失，这导致最终成熟和排卵失败。在顺铂处理的小鼠模型中，体外成熟以拯救卵母细胞导致成功的成熟和受精。这项研究首次显示了PTEN/Akt/FOXO 3通路参与顺铂治疗后的卵巢早衰，以及通过体外成熟进行挽救的可能性。
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.