Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Xu, Xulin; Chiu, Joyce; Chen, Shuai; Fang, Chao

doi:10.1111/bph.15493

Cited by 30 publications

(40 citation statements)

References 151 publications

(318 reference statements)

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“…Targeting extracellular PDIA1-, PDIA- and PDI17-dependent regulation of cancer cell adhesion may represent a novel, effective, personalized anti-adhesive and anti-metastatic therapy in cancers with high PDI expression. This notion agrees with an increasing interest in the molecular mechanisms of action of extracellular PDIs [ 51 ]. Further studies are required to explore the extracellular PDIs as anti-cancer targets.…”

Section: Discussionsupporting

confidence: 88%

Comparison of anti-cancer effects of novel protein disulphide isomerase (PDI) inhibitors in breast cancer cells characterized by high and low PDIA17 expression

et al. 2022

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Background Protein disulphide isomerases (PDIs) play an important role in cancer progression. However, the relative contribution of the various isoforms of PDI in tumorigenesis is not clear. Methods The content of PDI isoforms in 22 cancer cells lines was investigated using LC–MS/MS-based proteomic analysis. The effects of PDIA1, PDIA3 and PDIA17 inhibition on the proliferation, migration and adhesion of MCF-7 and MDA-MB-231 cells, identified as high and low PDIA17 expressing cells, respectively, were assessed using novel aromatic N-sulphonamides of aziridine-2-carboxylic acid derivatives as PDI inhibitors. Results PDIA1 and PDIA3 were the most abundant in cancer cell lysates and were also detected extracellularly in breast cancer cells (MDA-MB-231 and MCF-7). Some cancer cell lines (e.g., MCF-7, HT-29) showed upregulated expression of PDIA17, whereas in others (e.g., MDA-MB-231, 67NR), PDIA17 was not detected. The simultaneous inhibition of PDIA1 and PDIA3 showed similar anti-proliferative effects in MCF-7 and MDA-MB-231 breast cancer cells. However, the inhibition of PDIA1 and PDIA17 in the MCF-7 cell line resulted in more effective anti-adhesive and anti-proliferative effects. Conclusions PDIA1 and PDIA3 represent major isoforms of multiple cancer cells, and their non-selective inhibition displays significant anti-proliferative effects irrespective of whether or not PDIA17 is present. The more pronounced anti-adhesive effects of PDI inhibition in hormone-sensitive MCF-7 cells featured by higher levels of PDIs when compared to triple-negative MDA-MB-231 cells suggests that targeting extracellular PDIA1 and PDIA3 with or without additional PDIA17 inhibition may represent a strategy for personalized anti-adhesive, anti-metastatic therapy in cancers with high PDI expression.

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Section: Discussionsupporting

confidence: 88%

Comparison of anti-cancer effects of novel protein disulphide isomerase (PDI) inhibitors in breast cancer cells characterized by high and low PDIA17 expression

et al. 2022

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“…Besides interacting directly with fibrin and thrombin, quercetin and isoquercetin can exert their anticoagulant effect through inhibition protein disulfide isomerase (PDI). This ER-resident oxidoreductase is also expressed in platelets and endothelial cells ending up at their surface; its expression, when upregulated by thrombin stimulation or vascular injury, could contribute to thrombogenesis ( Xu et al, 2021 ). Strangely, when the flavonol inhibition of the reductase activity of recombinant PDI was assayed in vitro using a spectrometric measure of insulin aggregation in the presence of DTT, the IC 50 of quercetin, isoquercetin, rutin, and quercetin-3-glucuronide, were >100, 7.1, 6.1, and 5.9 μM, respectively, indicating that these C3 modification in the quercetin derivatives enhanced the anti-PDI activity ( Jasuja et al, 2012 ).…”

Section: Isoquercetin Is Quercetin Modifiedmentioning

confidence: 99%

Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize

Mbikay

Chrétien

2022

Front. Pharmacol.

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Isoquercetin and quercetin are secondary metabolites found in a variety of plants, including edible ones. Isoquercetin is a monoglycosylated derivative of quercetin. When ingested, isoquercetin accumulates more than quercetin in the intestinal mucosa where it is converted to quercetin; the latter is absorbed into enterocytes, transported to the liver, released in circulation, and distributed to tissues, mostly as metabolic conjugates. Physiologically, isoquercetin and quercetin exhibit antioxidant, anti-inflammatory, immuno-modulatory, and anticoagulant activities. Generally isoquercetin is less active than quercetin in vitro and ex vivo, whereas it is equally or more active in vivo, suggesting that it is primarily a more absorbable precursor to quercetin, providing more favorable pharmacokinetics to the latter. Isoquercetin, like quercetin, has shown broad-spectrum antiviral activities, significantly reducing cell infection by influenza, Zika, Ebola, dengue viruses among others. This ability, together with their other physiological properties and their safety profile, has led to the proposition that administration of these flavonols could prevent infection by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), or arrest the progression to severity and lethality of resulting coronavirus disease of 2019 (Covid-19). In silico screening of small molecules for binding affinity to proteins involved SARS-CoV-2 life cycle has repeatedly situated quercetin and isoquercetin near to top of the list of likely effectors. If experiments in cells and animals confirm these predictions, this will provide additional justifications for the conduct of clinical trials to evaluate the prophylactic and therapeutic efficacy of these flavonols in Covid-19.

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“…There is ample evidence that the presence of PDI in the extracellular space impacts blood clotting, virus entry and other pathophysiological events ( Gallina et al, 2002 ; Markovic et al, 2004 ; Furie & Flaumenhaft, 2014 ; Fraternale et al, 2021 ; Xu et al, 2021 ). In the ER, PDI is present in high concentration, up to 0.2–0.5 mM ( Lyles & Gilbert, 1991 ; Laurindo et al, 2012 ), making it a well-known marker of this compartment.…”

Section: Extracellular Functions Of Esc Residentsmentioning

confidence: 99%

Selective Secretion of KDEL-Bearing Proteins: Mechanisms and Functions

Palazzo

Sitia

Tempio

2022

Front. Cell Dev. Biol.

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In multicellular organisms, cells must continuously exchange messages with the right meaning, intensity, and duration. Most of these messages are delivered through cognate interactions between membrane and secretory proteins. Their conformational maturation is assisted by a vast array of chaperones and enzymes, ensuring the fidelity of intercellular communication. These folding assistants reside in the early secretory compartment (ESC), a functional unit that encompasses endoplasmic reticulum (ER), intermediate compartment and cis-Golgi. Most soluble ESC residents have C-terminal KDEL-like motifs that prevent their transport beyond the Golgi. However, some accumulate in the ER, while others in downstream stations, implying different recycling rates. Moreover, it is now clear that cells can actively secrete certain ESC residents but not others. This essay discusses the physiology of their differential intracellular distribution, and the mechanisms that may ensure selectivity of release.

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Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Cited by 30 publications

References 151 publications

Comparison of anti-cancer effects of novel protein disulphide isomerase (PDI) inhibitors in breast cancer cells characterized by high and low PDIA17 expression

Comparison of anti-cancer effects of novel protein disulphide isomerase (PDI) inhibitors in breast cancer cells characterized by high and low PDIA17 expression

Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize

Selective Secretion of KDEL-Bearing Proteins: Mechanisms and Functions

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