Endometrial cancer (EC) is one of the most common cancers among females worldwide. Advanced stage patients of EC have poor prognosis. Inevitable side effects and treatment tolerance of chemotherapy for EC remain to be addressed. Our results in this study showed that EC cells with higher tumor necrosis factor receptor-associated factor 4 (TRAF4) expression have lower sensitivity to poly ADP-ribose polymerase 1 (PARP1) inhibitors. Upon TRAF4 knockdown, the colony numbers of EC cells were markedly down-regulated, and the markers of DNA double-strand breakage were significantly up-regulated after the treatment of olaparib, a PARP1 inhibitor. TRAF4 knockdown reduced the phosphorylation of protein kinase B (Akt), promoted DNA double-strand breakage, and decreased levels of DNA repair related proteins, including phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). In addition, TRAF4′s effect on the sensitivity of EC cells to olaparib was further found to be mainly mediated by Akt phosphorylation. Moreover, in vivo results showed that TRAF4 knockdown enhanced the sensitivity of EC to PARP1 inhibitors using a mouse xenograft model. Collectively, our data suggest that combined application of TRAF4 knockdown and PARP1 inhibition can be used as a promising strategy for synthetic lethality in EC treatment.

中文翻译：

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TRAF4敲低触发协同致死性与同时抑制子宫内膜癌的PARP1。

子宫内膜癌（EC）是全球女性中最常见的癌症之一。EC的晚期患者预后较差。化疗对EC不可避免的副作用和治疗耐受性仍有待解决。我们在这项研究中的结果表明，具有较高肿瘤坏死因子受体相关因子4（TRAF4）表达的EC细胞对聚ADP-核糖聚合酶1（PARP1）抑制剂的敏感性较低。敲低TRAF4后，处理PARP1抑制剂olaparib后，EC细胞的集落数显着下调，DNA双链断裂的标志物显着上调。TRAF4敲低可减少蛋白激酶B（Akt）的磷酸化，促进DNA双链断裂，并降低DNA修复相关蛋白的水平，包括磷酸化DNA依赖性蛋白激酶（p-DNA-PK）和RAD51重组酶（RAD51）。另外，还发现TRAF4对EC细胞对奥拉帕尼的敏感性的作用主要是由Akt磷酸化介导的。此外，体内结果显示，使用小鼠异种移植模型，TRAF4敲低增强了EC对PARP1抑制剂的敏感性。总体而言，我们的数据表明TRAF4组合和PARP1抑制的组合应用可以作为EC治疗中合成杀伤力的有希望的策略。