Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1 alpha and protein disulfide isomerase suppresses the progression of cervical cancer
Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1 alpha and protein disulfide isomerase suppresses the progression of cervical cancer
复制标题
针对内质网氧化还原素-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
DOI：
10.1016/j.ebiom.2019.02.041
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Wang Lei
中科院分区：
文献类型：
--
作者：
Zhang Yini;Li Tao;Zhang Lihui;Shangguan Fugen;Shi Guizhi;Wu Xun;Cui Ya;Wang Xi'e;Wang Xi;Liu Yongzhang;Lu Bin;Wei Taotao;Wang Chih-chen;Wang Lei
树浆网（ER）氧化还原蛋白-1α (Ero1α)和蛋白二硫异构酶（PDI）是氧化蛋白折叠的关键途径，在许多癌症中高度表达。然而，针对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尚不清楚。方法采用创面愈合试验、跨井迁移和侵袭试验、异种移植试验评估细胞迁移、侵袭和肿瘤发生；凝胶过滤层析法、耗氧量法和细胞内折叠法检测Ero1α- pdi相互作用和Ero1α氧化酶活性。在此，我们报道了Ero1α的表达升高与人类宫颈癌的不良预后相关。敲除ero1通过下调h2o2相关的上皮-间质转化，减少宫颈癌细胞的生长、迁移和肿瘤发生。我们发现Ero1α的保守缬氨酸（Val） 101对Ero1α- pdi复合物的形成和Ero1α氧化酶的活性至关重要。Ero1α的Val101特异性参与PDI催化结构域的识别。Val101突变导致宫颈癌细胞内质网减少，氧化蛋白折叠延迟，h2o2水平降低，进一步损害细胞迁移、侵袭和肿瘤生长。我们的研究确定了识别PDI的关键残基Ero1α，这强调了氧化蛋白折叠在肿瘤发生中的分子机制，并为靶向Ero1α-PDI相互作用的癌症治疗提供了概念证明。本研究得到国家重点研发计划、国家自然科学基金、中国科学院青年创新促进会的支持。
BackgroundEndoplasmic 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.MethodsWe 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.FindingsHere, we report that elevated expression of Ero1α is correlated with poor prognosis in human cervical cancer. Knockout ofERO1Adecreases the growth, migration and tumorigenesis of cervical cancer cells, through downregulation of the H2O2-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 H2O2levels in the ER of cervical cancer cells and further impairs cell migration, invasion, and tumor growth.InterpretationOur 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.FundThis work was supported by National Key R&D Program of China, National Natural Science Foundation of China, and Youth Innovation Promotion Association, CAS.