C-Abl is not activated in DNA damage-induced and Tap63-mediated oocyte apoptosis in human ovary
C-Abl is not activated in DNA damage-induced and Tap63-mediated oocyte apoptosis in human ovary
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DOI：
10.1038/s41419-018-1026-7
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Oktem, Ozgur
中科院分区：
文献类型：
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作者：
Bildik, Gamze;Acilan, Ceyda;Oktem, Ozgur
关于c-Abl是否对诱导TAp 63介导的细胞凋亡至关重要以及用伊马替尼抑制c-Abl（其被设计用于抑制致癌激酶BCR-ABL和c-kit）是否保护卵母细胞免受小鼠中化疗诱导的细胞凋亡，文献中存在争议。没有关于这个问题的人类数据。因此，我们的目的是探讨化疗药物顺铂诱导的基因组损伤是否会激活c-Abl沿着TAp 63，以及伊马替尼对c-Abl的抑制是否会阻止顺铂诱导的人卵巢卵母细胞死亡和卵泡丢失。顺铂诱导卵母细胞和颗粒细胞DNA损伤，激活TAp 63和SAPK/JNK通路，并引发凋亡。然而，顺铂后TAp 63激活与c-Abl表达的任何增加无关。伊马替尼不能阻止顺铂诱导的颗粒细胞或卵母细胞凋亡。此外，用这种药物治疗导致形成形状奇异的卵泡，缺乏卵母细胞，并通过诱导颗粒细胞和卵母细胞凋亡增加卵泡闭锁。当卵巢组织样品与c-kit拮抗剂药物anti-CD 117孵育时，观察到类似的毒性作用，但与另一种c-Abl酪氨酸激酶抑制剂GNF-2孵育时没有观察到，GNF-2对c-kit缺乏抑制作用。对异种移植动物腹膜内给予伊马替尼，在人卵巢移植物的卵泡中产生了类似的组织形态学异常，并且当与顺铂联合给药时，不能防止顺铂诱导的卵泡丢失。我们的研究结果首次提供了该药物对人类卵巢毒性的分子证据。此外，本研究与之前的两例病例报告一起，在接受伊马替尼治疗时，患者对促性腺激素刺激的卵巢反应严重受损和卵巢早衰，进一步提高了对人类卵巢潜在性腺毒性的担忧，并敦促在年轻女性患者中谨慎使用。
There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.