Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells.
Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells.
复制标题
DOI：
10.1038/cddiscovery.2016.46
复制
发表时间：
2017
影响因子：
7
通讯作者：
Condon SM
中科院分区：
文献类型：
--
作者：
Mitsuuchi Y;Benetatos CA;Deng Y;Haimowitz T;Beck SC;Arnone MR;Kapoor GS;Seipel ME;Chunduru SK;McKinlay MA;Begley CG;Condon SM
凋亡抑制剂 (IAP) 蛋白在细胞增殖和分化中发挥着关键作用，在某些癌细胞系中拮抗 IAP 会导致细胞死亡。多种针对 cIAP1 杆状病毒 IAP 蛋白重复 3 (BIR3) 结构域的 IAP 拮抗剂化合物已进入临床试验。在这里，我们试图比较和对比选定的单价和二价 IAP 拮抗剂的生化活性，目的是确定这两类 IAP 拮抗剂候选药物之间的功能差异。通过使用单个共价键在 P4 位置结合单价部分，可以增加单价 IAP 拮抗剂的抗细胞 IAP1 (cIAP1) 和促凋亡活性。此外，无论药物浓度如何，与二价化合物治疗后观察到的结果相比，单价化合物治疗导致残留cIAP1水平始终较高。我们发现单价化合物治疗后剩余的残留 cIAP1 主要是肿瘤坏死因子 (TNF) 受体相关因子 2 (TRAF2) 相关的 cIAP1。因此，与单价化合物相比，二价化合物在抑制 TNF 诱导的 p65/NF-κB 激活方面更有效。此外，二价化合物 P4 位点连接链的延伸导致以与单价化合物类似的方式降解 TRAF2 相关 cIAP1 的能力降低。这一结果表明，特定的二价 IAP 拮抗剂而非单价化合物能够诱导 cIAP1 E3 泛素连接酶复合物的形成，并具有有效降解 TRAF2 相关 cIAP1 的能力。这些结果进一步表明，只有某些二价 IAP 拮抗剂优选用于靶向 TNF 依赖性信号传导以治疗癌症或传染病。
The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates. The anti-cellular IAP1 (cIAP1) and pro-apoptotic activities of monovalent IAP antagonists were increased by using a single covalent bond to combine the monovalent moieties at the P4 position. In addition, regardless of drug concentration, treatment with monovalent compounds resulted in consistently higher levels of residual cIAP1 compared with that seen following bivalent compound treatment. We found that the remaining residual cIAP1 following monovalent compound treatment was predominantly tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-associated cIAP1. As a consequence, bivalent compounds were more effective at inhibiting TNF-induced activation of p65/NF-κB compared with monovalent compounds. Moreover, extension of the linker chain at the P4 position of bivalent compounds resulted in a decreased ability to degrade TRAF2-associated cIAP1 in a manner similar to monovalent compounds. This result implied that specific bivalent IAP antagonists but not monovalent compounds were capable of inducing formation of a cIAP1 E3 ubiquitin ligase complex with the capacity to effectively degrade TRAF2-associated cIAP1. These results further suggested that only certain bivalent IAP antagonists are preferred for the targeting of TNF-dependent signaling for the treatment of cancer or infectious diseases.