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首页> 外文期刊>EBioMedicine >Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer
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Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer

机译：靶向内质网氧化还原蛋白1α和蛋白质二硫键异构酶之间的功能相互作用抑制宫颈癌的进展

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Background Endoplasmic reticulum (ER) oxidoreductin-1α (Ero1α) and protein disulfide isomerase (PDI) constitute the pivotal pathway of oxidative protein folding, and are highly expressed in many cancers. However, whether targeting the functional interplay between Ero1α and PDI could be a new approach for cancer therapy remains unknown. Methods We performed wound healing assays, transwell migration and invasion assays and xenograft assays to assess cell migration, invasion and tumorigenesis; gel filtration chromatography, oxygen consumption assay and in cells folding assays were used to detect Ero1α-PDI interaction and Ero1α oxidase activity. Findings Here, we report that elevated expression of Ero1α is correlated with poor prognosis in human cervical cancer. Knockout of ERO1A decreases the growth, migration and tumorigenesis of cervical cancer cells, through downregulation of the Hsub2/subOsub2/sub-correlated epithelial-mesenchymal transition. We identify that the conserved valine (Val) 101 of Ero1α is critical for Ero1α-PDI complex formation and Ero1α oxidase activity. Val101 of Ero1α is specifically involved in the recognition of PDI catalytic domain. Mutation of Val101 results in a reduced ER, retarded oxidative protein folding and decreased Hsub2/subOsub2/sub levels in the ER of cervical cancer cells and further impairs cell migration, invasion, and tumor growth. Interpretation Our study identifies the critical residue of Ero1α for recognizing PDI, which underlines the molecular mechanism of oxidative protein folding for tumorigenesis and provides a proof-of-concept for cancer therapy by targeting Ero1α-PDI interaction. Fund This work was supported by National Key R&D Program of China, National Natural Science Foundation of China, and Youth Innovation Promotion Association, CAS.
机译：背景内质网（ER）氧化还原蛋白1α（Ero1α）和蛋白质二硫键异构酶（PDI）构成了氧化蛋白质折叠的关键途径，并在许多癌症中高度表达。然而，靶向Ero1α和PDI之间的功能相互作用是否可能成为癌症治疗的新方法仍然未知。方法我们进行了伤口愈合测定，穿孔迁移和侵袭测定以及异种移植测定，以评估细胞迁移，侵袭和肿瘤发生。凝胶过滤色谱法，耗氧量测定法和细胞折叠测定法用于检测Ero1α-PDI相互作用和Ero1α氧化酶活性。在这里的发现，我们报告Ero1α的表达升高与人类宫颈癌的不良预后相关。通过下调H 2 O 2 相关的上皮-间充质转化，ERO1A的敲除降低了子宫颈癌细胞的生长，迁移和肿瘤发生。我们发现，Ero1α的保守缬氨酸（Val）101对于Ero1α-PDI复合物的形成和Ero1α氧化酶的活性至关重要。 Ero1α的Val101特别参与PDI催化域的识别。 Val101的突变会导致子宫颈癌细胞内质网减少，内质网氧化蛋白折叠减慢以及H 2 O 2 水平降低，并进一步损害细胞迁移，侵袭和转移。肿瘤生长。解释我们的研究确定了Ero1α识别PDI的关键残基，该残基强调了氧化蛋白折叠用于肿瘤发生的分子机制，并通过靶向Ero1α-PDI相互作用为癌症治疗提供了概念验证。基金这项工作得到了国家重点研究计划，国家自然科学基金和中国科学院青年创新促进会的支持。

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