The Role of Protein Disulfide Isomerase Inhibitors in Cancer Therapy

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-09-25 DOI:10.1002/cmdc.202400590

Qiuying Nie, Junwei Yang, Xiedong Zhou, Na Li, Junmin Zhang

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Abstract

Protein disulfide isomerase (PDI) is a member of the mercaptan isomerase family, primarily located in the endoplasmic reticulum (ER). At least 21 PDI family members have been identified. PDI plays a key role in protein folding, correcting misfolded proteins, and catalyzing disulfide bond formation, rearrangement, and breaking. It also acts as a molecular chaperone. Dysregulation of PDI activity is thus linked to diseases such as cancer, infections, immune disorders, thrombosis, neurodegenerative diseases, and metabolic disorders. In particular, elevated intracellular PDI levels can enhance cancer cell proliferation, metastasis, and invasion, making it a potential cancer marker. Cancer cells require extensive protein synthesis, with disulfide bond formation by PDI being a critical producer. Thus, cancer cells have higher PDI levels than normal cells. Targeting PDI can induce ER stress and activate the Unfolded Protein Response (UPR) pathway, leading to cancer cell apoptosis. This review discusses the structure and function of PDI, PDI inhibitors in cancer therapy, and the limitations of current inhibitors, proposing especially future directions for developing new PDI inhibitors.

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蛋白二硫异构酶抑制剂在癌症治疗中的作用

蛋白二硫异构酶（PDI）是巯基异构酶家族的成员，主要位于内质网（ER）中。目前已发现至少 21 个 PDI 家族成员。PDI 在蛋白质折叠、纠正错误折叠的蛋白质以及催化二硫键的形成、重排和断裂方面发挥着关键作用。它还充当分子伴侣。因此，PDI 活性失调与癌症、感染、免疫紊乱、血栓形成、神经退行性疾病和代谢紊乱等疾病有关。特别是，细胞内 PDI 水平的升高会促进癌细胞的增殖、转移和侵袭，使其成为一种潜在的癌症标志物。癌细胞需要大量的蛋白质合成，而 PDI 形成的二硫键是关键的生产者。因此，癌细胞的 PDI 水平高于正常细胞。以 PDI 为靶标可诱导 ER 应激，激活折叠蛋白反应（UPR）途径，从而导致癌细胞凋亡。这篇综述讨论了 PDI 的结构和功能、PDI 抑制剂在癌症治疗中的作用以及现有抑制剂的局限性，并特别提出了开发新的 PDI 抑制剂的未来方向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.