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.

中文翻译：

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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途径。

二硫键破坏剂（DDAs）是一种新的化学试剂，最近在动物模型中显示出对乳腺肿瘤具有活性。肿瘤生长的抑制与EGFR，HER2和HER3的下调以及Akt磷酸化的降低以及内质网应激的诱导有关。然而，尚不知道DDA如何在不影响未转化细胞的情况下触发癌细胞死亡。如此处所示，DDA是第一个通过转录和转录后机制激活外源细胞死亡途径而上调TRAIL受体DR5的化合物。在蛋白质水平，DDA改变DR5二硫键，以增加稳态DR5水平和寡聚，从而导致下游caspase 8和3活化。DDA和TRAIL协同作用杀死癌细胞，并对HER2 +癌细胞具有细胞毒性，并具有对EGFR / HER2酪氨酸激酶抑制剂拉帕替尼的抗性。对负责癌细胞的DDA选择性的机制的研究表明，在EGFR过表达的情况下，DDA诱导的DR5上调得到增强。DDA诱导的细胞毒性被MYC过表达强烈放大。这与MYC已知的TRAIL介导的细胞死亡增强作用相一致。总之，结果证明了DDA对致癌基因转化细胞具有选择性杀伤力，DDA介导的DR5上调和蛋白质稳定作用，并且DDA对耐药性癌细胞具有活性。我们的结果表明，DDA通过引起DR5二硫键改变的机制，在引起DR5积累和寡聚化以及诱导下游胱天蛋白酶激活和癌细胞死亡方面具有独特性。因此，DDA代表了一种新的癌症治疗方法。