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. 2020;2(3):103-115.
doi: 10.33696/cancerimmunol.2.023.

The Role of ERO1α in Modulating Cancer Progression and Immune Escape

Brennan D Johnson  1 , Werner J Geldenhuys  2   3 , Lori A Hazlehurst  1   2
Affiliations

The Role of ERO1α in Modulating Cancer Progression and Immune Escape

Brennan D Johnson et al. J Cancer Immunol (Wilmington). 2020.

Abstract

Endoplasmic reticulum oxidoreductin-1 alpha (ERO1α) was originally shown to be an endoplasmic reticulum (ER) resident protein undergoing oxidative cycles in concert with protein disulfide isomerase (PDI) to promote proper protein folding and to maintain homeostasis within the ER. ERO1α belongs to the flavoprotein family containing a flavin adenine dinucleotide utilized in transferring of electrons during oxidation-reduction cycles. This family is used to maintain redox potentials and protein homeostasis within the ER. ERO1α's location and function has since been shown to exist beyond the ER. Originally thought to exist solely in the ER, it has since been found to exist in the golgi apparatus, as well as in exosomes purified from patient samples. Besides aiding in protein folding of transmembrane and secretory proteins in conjunction with PDI, ERO1α is also known for formation of de novo disulfide bridges. Public databases, such as the Cancer Genome Atlas (TCGA) and The Protein Atlas, reveal ERO1α as a poor prognostic marker in multiple disease settings. Recent evidence indicates that ERO1α expression in tumor cells is a critical determinant of metastasis. However, the impact of increased ERO1α expression in tumor cells extends into the tumor microenvironment. Secretory proteins requiring ERO1α expression for proper folding have been implicated as being involved in immune escape through promotion of upregulation of programmed death ligand-1 (PD-L1) and stimulation of polymorphonuclear myeloid derived suppressor cells (PMN-MDSC's) via secretion of granulocytic colony stimulating factor (G-CSF). Hereby, ERO1α plays a pivotal role in cancer progression and potentially immune escape; making ERO1α an emerging attractive putative target for the treatment of cancer.

Keywords: Cancer; Cancer therapeutics; ER stress; ERO1; Immune resistance.

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Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:
Upon Phosphorylation of Serine 145 by FAM20C Kinase, ERO1α can return to the endoplasmic reticulum (ER). Above is an illustration of the interaction occurring between active site of ERO1α, PDI, and Glutathione (GSH). This reaction is also capable of occurring in the reverse direction resulting in redox equilibrium inside the ER. (Red circle is the phosphorylation site of ERO1α at serine 145 via FAM20C kinase, Black squares connected by blue lines are active disulfide bridges required for redox to occur, and black arrows are representative of electron flow when ERO1α is being reduced.
Figure 2:
Figure 2:
A) The structure of ERO1a (3AHQ.pdb) with the FAD binding site shown; B) the orientation of the Cys394-Cys397 with FAD; C) the proposed catalytic scheme of FAD and disulfide bond formation.
Figure 3:
Figure 3:
Top Left Panel represents survival data for Lung Adenocarcinoma in respect to ERO1α, Top Right Panel represents Esophageal Carcinoma, Bottom Left Panel represents survival data for hepatocellular carcinoma, and Bottom Right Panel represents survival data for diffuse B-cell lymphoma. Kaplan-Meyer Plots above were plotted using ERO1α gene filter in GEPIA, which obtains data from TCGA and GTEx databases.
Figure 4:
Figure 4:
Structure of EN460, the first ERO1α inhibitor, and the azide derivative PB-EN-10.
See this image and copyright information in PMC

References

    1. Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC—challenges to implementing ctDNA-based screening and MRD detection. Nature Reviews Clinical Oncology. 2018. September;15(9):577–86. - PubMed
    1. Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discovery. 2017. December 1;7(12):1394–403. - PMC - PubMed
    1. Nair RR, Tolentino J, Hazlehurst LA. The bone marrow microenvironment as a sanctuary for minimal residual disease in CML. Biochemical Pharmacology. 2010. September 1;80(5):602–12. - PMC - PubMed
    1. Ootsuka S, Asami S, Sasaki T, Yoshida Y, Nemoto N, Shichino H, et al. Useful markers for detecting minimal residual disease in cases of neuroblastoma. Biological and Pharmaceutical Bulletin. 2008. June 1;31(6):1071–4. - PubMed
    1. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell. 2020. April 13;37(4):443–55. - PMC - PubMed

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