BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs
BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs
复制标题
DOI：
10.1073/pnas.1415178111
复制
发表时间：
2014-11-18
影响因子：
11.1
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
--
作者：
Leibowitz, Brian;Qiu, Wei;Zhang, Lin
结直肠肿瘤的发生是由腺瘤性结肠息肉病 (APC) 肿瘤抑制途径的基因改变驱动的，并可被非甾体抗炎药 (NSAID) 有效抑制。然而，非甾体抗炎药如何预防结直肠肿瘤的发生仍然不清楚。我们发现外源性细胞凋亡途径和 BH3 相互作用域死亡激动剂 (BID) 在接受 NSAID 治疗的患者的腺瘤中被激活。 BID 的缺失消除了 APC(Min/+) 小鼠中 NSAID 介导的肿瘤抑制、生存益处和肿瘤起始干细胞的凋亡。 BID 介导的外源性和内源性细胞凋亡途径之间的串扰是 NSAID 选择性杀死肿瘤细胞的原因。我们进一步证明，NSAID 会在癌症和正常细胞中诱导死亡受体信号传导，但仅在 APC 缺陷的细胞中激活 BID，并随后激活 c-Myc。我们的研究结果表明，NSAIDs 通过死亡受体信号传导和看门人突变触发的 BID 介导的合成致死作用来抑制肠道肿瘤发生，并为开发更有效的癌症预防策略和药物提供了理论依据。
Colorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.