文章目录

抑制cFLIP和激活DR5使衰老癌细胞对衰老溶解敏感

原文发布日期：2022-11-22

英文摘要：

摘要翻译：

原文链接：

文章：

抑制cFLIP和激活DR5使衰老癌细胞对衰老溶解敏感

cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis

原文发布日期：2022-11-22

英文摘要：

Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this ‘one-two punch’ cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

摘要翻译：

用于促进癌细胞衰老的药物，即senolytics，因其能够杀死已进入衰老状态的细胞而备受关注。然而，尽管如此，这类药物的应用仍面临诸多挑战，主要是因为目前缺乏能够广泛作用于不同癌细胞类型的senolytic药物。利用基于CRISPR/Cas9的基因筛选方法，在不同的癌前细胞模型中进行研究，我们发现，损失死亡受体抑制剂cFLIP是衰老癌细胞普遍存在的易病性。癌前细胞在NF-κB介导的DR5死亡受体表达上调以及TRAIL等抗凋亡分子的上调下被编程化地诱导细胞凋亡，但因cFLIP蛋白表达量的增加而得以免于这种结局。通过注射抗体会激活DR5信号通路，该信号通路可以通过抑制BRD2进而增强其活性，从而高效地杀死多种癌前癌细胞。此外，衰老细胞通过释放细胞因子等方式，诱导非衰老邻近细胞对DR5抗原活化剂产生易感性，这种效应在旁观者效应中得以体现。我们通过结合促进癌细胞衰老的治疗与DR5激活，在不同的动物模型中验证了这一“一击两落”的癌症治疗方法。