Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Rogel Cancer Center, Ann Arbor, MI 48109, United States.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Rogel Cancer Center, Ann Arbor, MI 48109, United States; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
Pharmacol Ther. 2020 Jun;210:107525. doi: 10.1016/j.pharmthera.2020.107525. Epub 2020 Mar 20.
Protein folding in the endoplasmic reticulum is an oxidative process that relies on protein disulfide isomerase (PDI) and endoplasmic reticulum oxidase 1 (ERO1). Over 30% of proteins require the chaperone PDI to promote disulfide bond formation. PDI oxidizes cysteines in nascent polypeptides to form disulfide bonds and can also reduce and isomerize disulfide bonds. ERO1 recycles reduced PDI family member PDIA1 using a FAD cofactor to transfer electrons to oxygen. ERO1 dysfunction critically affects several diseases states. Both ERO1 and PDIA1 are overexpressed in cancers and implicated in diabetes and neurodegenerative diseases. Cancer-associated ERO1 promotes cell migration and invasion. Furthermore, the ERO1-PDIA1 interaction is critical for epithelial-to-mesenchymal transition. Co-expression analysis of ERO1A gene expression in cancer patients demonstrated that ERO1A is significantly upregulated in lung adenocarcinoma (LUAD), glioblastoma and low-grade glioma (GBMLGG), pancreatic ductal adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP) cancers. ERO1Α knockdown gene signature correlates with knockdown of cancer signaling proteins including IGF1R, supporting the search for novel, selective ERO1 inhibitors for the treatment of cancer. In this review, we explore the functions of ERO1 and PDI to support inhibition of this interaction in cancer and other diseases.
内质网中的蛋白质折叠是一个氧化过程，依赖于蛋白质二硫键异构酶（PDI）和内质网氧化酶 1（ERO1）。超过 30%的蛋白质需要伴侣蛋白 PDI 来促进二硫键形成。PDI 将新生多肽中的半胱氨酸氧化形成二硫键，并且还可以还原和异构化二硫键。ERO1 使用 FAD 辅助因子回收还原的 PDIA1 家族成员 PDIA1，将电子转移到氧气上。ERO1 功能障碍严重影响多种疾病状态。ERO1 和 PDIA1 在癌症中过度表达，并与糖尿病和神经退行性疾病有关。与癌症相关的 ERO1 促进细胞迁移和侵袭。此外，ERO1-PDIA1 相互作用对于上皮细胞向间充质转化至关重要。对癌症患者 ERO1A 基因表达的共表达分析表明，ERO1A 在肺腺癌（LUAD）、胶质母细胞瘤和低级别神经胶质瘤（GBMLGG）、胰腺导管腺癌（PAAD）和肾肾乳头细胞癌（KIRP）中显著上调。ERO1Α 敲低基因特征与包括 IGF1R 在内的癌症信号蛋白的敲低相关，支持寻找新型、选择性的 ERO1 抑制剂来治疗癌症。在这篇综述中，我们探讨了 ERO1 和 PDI 的功能，以支持抑制这种在癌症和其他疾病中的相互作用。
