ERO1 alpha deficiency impairs angiogenesis by increasing N-glycosylation of a proangiogenic VEGFA

Varone, Ersilia; Chernorudskiy, Alexander; Cherubini, Alessandro; Cattaneo, Angela; Bachi, Ángela; Fumagalli, Stefano; Erol, Gizem; Gobbi, Marco; Lenardo, Michael J.; Borgese, Nica; Zito, Ester

doi:10.1016/j.redox.2022.102455

Cited by 10 publications

(7 citation statements)

References 39 publications

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“… 1 To track ER redox poise and identify differences among wild-type (WT), SEPN1 KO, ERO1 KO, and double (SEPN1, ERO1) KO (DKO) HeLa cells ( Figure 2 D), we used the ratiometric redox sensor ER-localized roGFP2. 22 , 23 The redox changes of the sensor in live cells were measured by comparing sensor emission intensity at 525 nm when excited at 405 (excitation [Ex] 405 emission[Em] 525 ) and 488 (Ex 488 Em 525 ) nm. The oxidation within ER was slightly decreased in ERO1 KO, as was also suggested previously, 24 and in DKO cells.…”

Section: Resultsmentioning

confidence: 99%

“…SEPN1 KO, ERO1 KO and DKO HeLa cells were described elsewhere. 1 , 3 , 23 HEK 293T cells were transfected with ERO1-Lα CRISPR-Cas9 KO plasmids (SC-401747 for human Santa Cruz Biotechnology). The plasmids were co-transfected with homology-directed repair HDR (SC-401747-HDR for human, Santa Cruz Biotechnology) plasmids, which led to the insertion of puromycin resistance gene and red fluorescent protein (RFP) gene as in.…”

Section: Methodsmentioning

confidence: 99%

“…The plasmids were co-transfected with homology-directed repair HDR (SC-401747-HDR for human, Santa Cruz Biotechnology) plasmids, which led to the insertion of puromycin resistance gene and red fluorescent protein (RFP) gene as in. 23 , 55 WT and SEPN1 KD C2C12 were described elsewhere. 2 Cells were routinely tested for Mycoplasma by PCR.…”

Section: Methodsmentioning

confidence: 99%

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SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA

Germani,

Van Ho,

Cherubini

et al. 2024

Cell Reports Medicine

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA

Germani,

Van Ho,

Cherubini

et al. 2024

Cell Reports Medicine

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“…H 2 O 2 generated by ERO1α during oxidative folding in the ER freely diffuses into the cytoplasm, where it then stabilizes HIF-1α by inhibiting prolyl hydroxylases (PHDs) [107,108]. In addition, ERO1α has been reported to modulate VEGF via the S1PR1-STAT3 signaling pathway in liver cancer cells [58], and the deficiency of ERO1α in cervical cancer cells impaired the secretion of VEGF due to N-hyper-glycosylation [109].…”

Section: Angiogenesismentioning

confidence: 99%

Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer

Chen,

Sharma,

Weiher

et al. 2024

J Exp Clin Cancer Res

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A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly upregulated in various cancer types and associated with a significantly worse prognosis. Of importance, under ER stress, the functional interplay of ERO1α/PDI axis plays a pivotal role to orchestrate proper protein folding and other key processes. Multiple lines of evidence propose ERO1α as an attractive potential target for cancer treatment. However, the unavailability of specific inhibitor for ERO1α, its molecular inter-relatedness with closely related paralog ERO1β and the tightly regulated processes with other members of flavoenzyme family of enzymes, raises several concerns about its clinical translation. Herein, we have provided a detailed description of ERO1α in human cancers and its vulnerability towards the aforementioned concerns. Besides, we have discussed a few key considerations that may improve our understanding about ERO1α in tumors.

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“…Recent secretomic analyses indicate that the lack of ERO1 in breast cancer cells has no major impact in normoxia but impairs different angiogenic factors in hypoxia, suggesting a selective effect on angiogenesis. At the molecular level, the lack of ERO1 not only impairs the intermolecular disulfide bonds of VEGFA but also promotes a hyper-N-glycosylation of the isoform VEGF 121 that blunts its secretion ( 35 ). This explains why ERO1-deficient TNBC xenografts have decreased vasculogenesis, together with a reduced ability to generate lung metastases, suggesting that ERO1 inhibition might be a good tool to selectively impair angiogenesis in solid tumors and limit metastasis ( 34 ).…”

Section: Unfolded Protein Response In Cancermentioning

confidence: 99%

ER stress as a trigger of UPR and ER-phagy in cancer growth and spread

Cherubini¹,

Zito²

2022

Front. Oncol.

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Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The endoplasmic reticulum (ER) is the organelle where proteins undergo post-translational modifications and are folded and exported to the secretory pathway. Its environment and activity are therefore fundamental for proteostasis, i.e., the plethora of mechanisms controlling protein formation, folding, degradation, and secretion, needed to assure protein balance and cellular health. In different tumor-related conditions, such as after the activation of oncogenes or under hypoxia and nutrient deprivation, the ER experiences stress, triggered by a high load of proteins to be folded compared to the limited folding capacity of the organelle. As a consequence, three ER membrane sensors and the related unfolded protein response (UPR) are activated. The UPR comprises a complex interconnection between signal transduction pathways that promote a homeostatic response that acts by increasing the amount of protein chaperones and of proteins involved in ER-associated protein degradation (ERAD) on one hand and attenuating protein translation on the other. ER-phagy, literally “eating” the ER, is part of another homeostatic response consisting of the clearance of non-functional ER portions including misfolded proteins. This response is also activated by a set of dedicated ER-phagy receptors after ER stimuli, which overlap the stimuli generating ER stress. Thus, the UPR and ER-phagy are two closely related homeostatic mechanisms that cooperate in re-establishing ER homeostasis. However, while the role of the UPR in favoring cancer growth and thriving by promoting angiogenesis, metastasis, chemotherapy resistance, and epithelial-to-mesenchymal transition is consolidated, that of ER-phagy is still in its infancy. This essay provides an overview of emerging concepts on ER stress, the UPR, and ER-phagy and their crosstalk in tumorigenesis. We also critically review new findings on their pharmacological targeting in cancer.

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ERO1 alpha deficiency impairs angiogenesis by increasing N-glycosylation of a proangiogenic VEGFA

Cited by 10 publications

References 39 publications

SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA

SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA

Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer

ER stress as a trigger of UPR and ER-phagy in cancer growth and spread

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