Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.
Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.
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ERp44、PDIA1 和 AGR2 抑制剂可诱导二硫键介导的死亡受体 4 和 5 寡聚化以及癌细胞死亡。
DOI：
10.1016/j.canlet.2022.215604
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发表时间：
2022
期刊：
影响因子：
9.7
通讯作者：
Law,BrianK
中科院分区：
文献类型：
--
作者：
Law,MaryE;Yaaghubi,Elham;Ghilardi,AmandaF;Davis,BradleyJ;Ferreira,RenanB;Koh,Jin;Chen,Sixue;DePeter,SadieF;Schilson,ChristopherM;Chiang,Chi-Wu;Heldermon,CoyD;Nørgaard,Peter;Castellano,RonaldK;Law,BrianK
乳腺癌死亡率仍然高得令人无法接受，这表明需要更安全和更有效的治疗药物。二硫键破坏剂（DDA）先前被鉴定为一类新型抗癌化合物，其选择性地杀死过表达表皮生长因子受体（EGFR）或其家族成员HER2的癌症。DDA通过EGFR、HER2和HER3的平行下调以及死亡受体4和5（DR4/5）的激活/寡聚化杀死EGFR+和HER2+癌细胞。然而，DDAs介导这些效应的机制尚不清楚。使用生物素化的DDA的亲和纯化分析揭示，蛋白质二硫键异构酶（PDI）家族成员AGR2、PDIA1和ERp44是DDA靶蛋白。进一步的分析表明，shRNA介导的AGR2和ERp44的敲低，或ERp44突变体的表达，增强基础DR5寡聚化。乳腺癌细胞的DDA处理破坏PDIA1和ERp44与其客户蛋白的混合二硫键。总之，本文的结果揭示了DDA作为第一小分子、AGR2和ERp44的活性位点抑制剂，并证明了AGR2和ERp44在调节DR4和DR5的活性、稳定性和定位以及半胱天冬酶8的活化中的作用。
Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.