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Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1? and protein disulfide isomerase suppresses the progression of cervical cancer.

ABSTRACT: BACKGROUND:Endoplasmic reticulum (ER) oxidoreductin-1? (Ero1?) 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 Ero1? 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 Ero1?-PDI interaction and Ero1? oxidase activity. FINDINGS:Here, we report that elevated expression of Ero1? 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 H2O2-correlated epithelial-mesenchymal transition. We identify that the conserved valine (Val) 101 of Ero1? is critical for Ero1?-PDI complex formation and Ero1? oxidase activity. Val101 of Ero1? is specifically involved in the recognition of PDI catalytic domain. Mutation of Val101 results in a reduced ER, retarded oxidative protein folding and decreased H2O2 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 Ero1? 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 Ero1?-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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6443025 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer.

Zhang Yini Y Li Tao T Zhang Lihui L Shangguan Fugen F Shi Guizhi G Wu Xun X Cui Ya Y Wang Xi'e X Wang Xi X Liu Yongzhang Y Lu Bin B Wei Taotao T Wang Chih-Chen CC Wang Lei L

EBioMedicine 20190227

<h4>Background</h4>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.<h4>Methods</h4>We performed wound healing assays, transwell migration and invasion assays and xenograft assays to assess cell migration, invasion and tumo ...[more]

PMID: 30826359

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Project description:BACKGROUND: Protein disulfide isomerase (PDI), is sorted to be enzymatic chaperone for reconstructing misfolded protein in endoplasmic reticulum lumen. Recently, PDI has been identified as a link between misfolded protein and neuron apoptosis. However, the potential for PDI to be involved in the pathogenesis of prion disease remains unknown. In this study, we propose that PDI may function as a pleiotropic regulator in the cytotoxicity induced by mutated prion proteins and in the pathogenesis of prion diseases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate potential alterations of PDI in prion diseases, the levels of PDI and relevant apoptotic executors in 263K infected hamsters brain tissues were evaluated with the use of Western blots. Abnormal upregulation of PDI, Grp78 and Grp58 was detected. Dynamic assays of PDI alteration identified that the upregulation of PDI started at the early stage and persistently increased till later stage. Obvious increases of PDI and Grp78 levels were also observed in cultured cells transiently expressing PrP mutants, PrP-KDEL or PrP-PG15, accompanied by significant cytotoxicities. Excessive expression of PDI partially eased ER stress and cell apoptosis caused by accumulation of PrP-KDEL, but had less effect on cytotoxicity induced by PrP-PG15. Knockdown of endogenous PDI significantly amended cytotoxicity of PrP-PG15, but had little influence on that of PrP-KDEL. A series of membrane potential assays found that apoptosis induced by misfolded PrP proteins could be regulated by PDI via mitochondrial dysfunction. Moreover, biotin-switch assays demonstrated active S-nitrosylated modifications of PDI (SNO-PDI) both in the brains of scrapie-infected rodents and in the cells with misfolded PrP proteins. CONCLUSION/SIGNIFICANCE: Current data in this study highlight that PDI and its relevant executors may function as a pleiotropic regulator in the processes of different misfolded PrP proteins and at different stages during prion infection. SNO-PDI may feed as an accomplice for PDI apoptosis.

Dataset Information

Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1? and protein disulfide isomerase suppresses the progression of cervical cancer.

Publications

Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer.

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