Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction
Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction
复制标题
DOI：
10.1038/nm1197-1228
复制
发表时间：
1997-11-01
期刊：
影响因子：
82.9
通讯作者：
Tilly, JL
中科院分区：
文献类型：
--
作者：
Perez, GI;Knudson, CM;Tilly, JL
由于卵母细胞破坏而导致的女性不育是化疗的不幸后果，在许多情况下是不可避免的。我们发现未受精的小鼠卵母细胞暴露于治疗水平的抗肿瘤药物，阿霉素（DXR），发生凋亡；然而，当用DXR处理时，受精的卵母细胞不会启动凋亡，而是进入细胞周期停滞。DXR诱导的卵母细胞凋亡可被神经酰胺促进细胞死亡的抑制剂鞘氨醇-1-磷酸阻断。在体内和体外实验中，bax缺乏而不是p53缺失的雌性小鼠的卵母细胞对dxr诱导的细胞凋亡表现出完全的抗性。用特定的半胱天冬酶肽抑制剂预处理卵母细胞也可以消除DXR对细胞的凋亡反应。这些发现表明，化疗引起的卵母细胞破坏可以通过操纵凋亡相关信号通路来预防。
Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.