ER Stress is Involved in Epithelial-To-Mesenchymal Transition of Alveolar Epithelial Cells Exposed to a Hypoxic Microenvironment

Delbrel, Eva; Uzunhan, Y.; Soumaré, Abdoulaye; Gille, Thomas; Marchant, Dominique; Planès, Carole; Boncoeur, Émilie

doi:10.3390/ijms20061299

Cited by 35 publications

(28 citation statements)

References 32 publications

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“… 37 While hypoxia triggers the UPR in a range of targets including airway epithelial cells, the mechanism(s) by which this occurs is/are incompletely understood. 38 ROS generated in the context of hypoxia may modulate UPR activation by direct or indirect effects on BiP and by impaired disulphide bond formation. 39 40 The redox-sensitive chaperone PDI becomes reduced during protein folding; it recovers by transferring electrons to ERO1 (ER oxidoreductin), which then requires molecular oxygen to become reoxidised and regain function.…”

Section: Er Stress Triggers Relevant To Respiratory Diseasementioning

confidence: 99%

Role of unfolded proteins in lung disease

Bradley

Stokes

Marciniak

et al. 2020

Thorax

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The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

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Section: Er Stress Triggers Relevant To Respiratory Diseasementioning

confidence: 99%

Role of unfolded proteins in lung disease

Bradley

Stokes

Marciniak

et al. 2020

Thorax

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“…On the other hand, the orchestrating role of ER stress in EMT initiation has been well established ( Figure 1 ). Hypoxia is a factor driving pro-EMT transcription factors, as well as the activation of ER stress markers both in vivo in rat lungs and in vitroin alveolar epithelial cells (AECs) [ 28 ]. The involvement of hypoxia and intracellular calcium in EMT induction of AECs was mainly through the activation of ER stress and hypoxia-induced factor (HIF)-signalling pathways [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hypoxia is a factor driving pro-EMT transcription factors, as well as the activation of ER stress markers both in vivo in rat lungs and in vitroin alveolar epithelial cells (AECs) [ 28 ]. The involvement of hypoxia and intracellular calcium in EMT induction of AECs was mainly through the activation of ER stress and hypoxia-induced factor (HIF)-signalling pathways [ 28 ]. ER stress induced EMT in AECs through Src-dependent pathways, results in fibroblast accumulation in pulmonary fibrosis [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, enhanced ER stress was responsible for induction of EMT in human lens epithelial cells [ 30 ]. ER stress up regulated the EMT markers such as N-cadherin, vimentin, fibronectin and α-SMA [ 28 ]. Histone deacetylases (HDACs) participate in the regulation of dynamic equilibrium state of histone or non-histone acetylation/deacetylation.…”

Section: Introductionmentioning

confidence: 99%

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Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT

Gundamaraju

Azimi

et al. 2020

Biomedicines

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The majority of cellular responses to external stimuli are mediated by receptors such as G protein-coupled receptors (GPCRs) and systems including endoplasmic reticulum stress (ER stress). Since GPCR signalling is pivotal in numerous malignancies, they are widely targeted by a number of clinical drugs. Cancer cells often negatively modulate GPCRs in order to survive, proliferate and to disseminate. Similarly, numerous branches of the unfolded protein response (UPR) act as pro-survival mediators and are involved in promoting cancer progression via mechanisms such as epithelial to mesenchymal transition (EMT). However, there are a few proteins among these groups which impede deleterious effects by orchestrating the pro-apoptotic phenomenon and paving a therapeutic pathway. The present review exposes and discusses such critical mechanisms and some of the key processes involved in carcinogenesis.

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“…ER stress induces EMT in AECs, at least in part through Src-dependent pathways, thereby demonstrating its role in fibroblast accumulation in pulmonary fibrosis [20]. Hypoxia was another factor driving pro-EMT transcription factors, as well as the activation of ER stress markers both in vivo in rat lungs and in vitro in aleveolar epithelial cells [21]. Hence hypoxia and intracellular calcium are both involved in EMT induction of AECs, mainly through the activation of ER stress and hypoxiainduced factor (HIF)-signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

The Good among the Bad and the Ugly: The Unsung Heroes in ER Stress, GPCR and EMT

Gundamaraju¹,

Lu²,

Eri³

2020

Preprint

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The majority of cellular responses to external stimuli are mediated by receptors such as G protein-coupled receptors (GPCRs) and systems including endoplasmic reticular stress (ER stress). Since GPCR signalling is pivotal in numerous malignant pathologies, they are targeted by a number of clinically used drugs. Cancer cells often negatively modulate GPCRs in order to survive, proliferate and to disseminate. Similarly, numerous branches of the unfolded protein response (UPR) act as pro-survival mediators and are involved in promoting cancer progression via mechanisms such as epithelial mesenchymal transition (EMT). However, there are a few proteins among these groups which impede deleterious effects by orchestrating the pro-apoptotic phenomenon and paving a therapeutic pathway. The present review exposes and discusses such critical mechanisms and some of the key processes involved in carcinogenesis.

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ER Stress is Involved in Epithelial-To-Mesenchymal Transition of Alveolar Epithelial Cells Exposed to a Hypoxic Microenvironment

Cited by 35 publications

References 32 publications

Role of unfolded proteins in lung disease

Role of unfolded proteins in lung disease

Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT

The Good among the Bad and the Ugly: The Unsung Heroes in ER Stress, GPCR and EMT

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