Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.
Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.
复制标题
二硫键破坏剂激活肿瘤坏死家族相关的凋亡诱导配体/死亡受体 5 通路。
DOI：
10.1038/s41420-019-0228-9
复制
发表时间：
2019
影响因子：
7
通讯作者：
Law,BrianK
中科院分区：
文献类型：
--
作者：
Wang,Mengxiong;Law,MaryE;Davis,BradleyJ;Yaaghubi,Elham;Ghilardi,AmandaF;Ferreira,RenanB;Chiang,Chi-Wu;Guryanova,OlgaA;Kopinke,Daniel;Heldermon,CoyD;Castellano,RonaldK;Law,BrianK
二硫键干扰剂(DDAs)是一类新的化学试剂，最近在动物模型中被证明具有抗乳腺肿瘤的活性。抑制肿瘤生长与下调EGFR、HER2和HER3，减少Akt磷酸化，以及诱导内质网应激有关。然而，目前尚不清楚双酚A如何在不影响未转化细胞的情况下触发癌细胞死亡。正如这里所证明的，DDAS是第一个被发现的化合物，它通过转录和转录后机制上调TRAIL受体DR5，激活外源性细胞死亡途径。在蛋白质水平上，DDAS改变DR5的二硫键以增加稳态DR5水平和寡聚，导致下游caspase8和3的激活。DDA和TRAIL协同杀死癌细胞，并对对EGFR/HER2酪氨酸激酶抑制剂Lapatinib产生获得性耐药性的HER2+癌细胞具有细胞毒作用。对癌细胞DDA选择性机制的研究表明，在EGFR过度表达的背景下，DDA诱导的DR5上调是增强的。MYC的过度表达强烈地放大了DDA诱导的细胞毒作用。这与已知的MYC对TRAIL介导的细胞死亡的增强是一致的。综上所述，这些结果显示了DDA对癌基因转化细胞的选择性致死性、DDA介导的DR5上调和蛋白质稳定性，以及DDAS对耐药癌细胞的活性。我们的结果表明，在引起DR5积聚和寡聚以及通过改变DR5二硫键的机制诱导下游caspase激活和癌细胞死亡方面，DDAS是独一无二的。因此，DDAS代表了癌症治疗的一种新的治疗方法。
Disulfide bond-disrupting agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. Blockade of tumor growth is associated with downregulation of EGFR, HER2, and HER3 and reduced Akt phosphorylation, as well as the induction of endoplasmic reticulum stress. However, it is not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through transcriptional and post-transcriptional mechanisms to activate the extrinsic cell death pathway. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression. DDA-induced cytotoxicity is strongly amplified by MYC overexpression. This is consistent with the known potentiation of TRAIL-mediated cell death by MYC. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation, and protein stabilization, and that DDAs have activity against drug-resistant cancer cells. Our results indicate that DDAs are unique in causing DR5 accumulation and oligomerization and inducing downstream caspase activation and cancer cell death through mechanisms involving altered DR5 disulfide bonding. DDAs thus represent a new therapeutic approach to cancer therapy.