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.
Highlights
The failure to eradicate minimal residual disease often located at metastatic sites and/or the bone marrow niche continues to be a clinical barrier for successful treatments in cancer [1,2,3,4]
Reported to co-localize with protein disulfide isomerase (PDI) in the endoplasmic reticulum (ER) lumen [16], ERO1α has more recently been shown to localize in the golgi apparatus [52], in proximity to the mitochondrial associated Endoplasmic Reticulum membranes (MAM), but only under oxidizing and normoxic conditions [56], and was identified from purified exosomes from bladder cancer cells, liver cancer cells, and squamous cell carcinoma cells
In a recent publication; Tanaka et al [37] demonstrated that ERO1α plays a pivotal role in PMNMDSC induction via up-regulation of granulocytic colony stimulating factor (G-CSF) production from cancer cells in collaboration with PDI
Summary
The failure to eradicate minimal residual disease often located at metastatic sites and/or the bone marrow niche continues to be a clinical barrier for successful treatments in cancer [1,2,3,4]. Reported to co-localize with PDI in the ER lumen [16], ERO1α has more recently been shown to localize in the golgi apparatus [52], in proximity to the mitochondrial associated Endoplasmic Reticulum membranes (MAM), but only under oxidizing and normoxic conditions [56], and was identified from purified exosomes from bladder cancer cells, liver cancer cells, and squamous cell carcinoma cells (exocarto and protein atlas).
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