Endoplasmic reticulum stress responses in placentation - A true balancing act

Bastida-Ruiz, Daniel; Aguilar, Elizabeth; Ditisheim, Agnès; Yart, Lucile; Cohen, Marie

doi:10.1016/j.placenta.2017.07.004

Cited by 36 publications

(39 citation statements)

References 72 publications

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“…Confirming that this is not just an in vitro effect, the placentae from women with Antiphospholipid Antibody Syndrome contained a substantially higher level of misfolded proteins than control placentae. Endoplasmic reticulum stress is characterized by the misfolding of proteins in the endoplasmic reticulum and a physiologic response called the unfolded protein response [37,38]. Thus, it seems that one mechanism by which antiphospholipid antibodies affect placental function is by increasing endoplasmic reticulum stress in the syncytiotrophoblast.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies

et al. 2020

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Antiphospholipid autoantibodies (aPLs), a major maternal risk factor for preeclampsia, are taken into the syncytiotrophoblast where they bind intracellular vesicles and mitochondria. Subsequently, large quantities of extracellular vesicles (EVs) extruded from syncytiotrophoblast into the maternal circulation are altered such that they cause maternal endothelial cell activation. However, the mechanism driving this change is unknown. First trimester placental explants were treated with aPL for 18 h. The EVs were then collected by different centrifugation. The levels of HSP 70, misfolded proteins, caspase 8 activity, and Mixed Lineage Kinase domain-Like (MLKL) were measured in placental explants and EVs. In addition, the levels of TNF-α and CD95 in conditioned medium were also measured. Treating placental explants with aPL caused an increase in levels of HSP 70, misfolded proteins and MLKL in placental explants and EVs. Increased activity of caspase 8 was also seen in placental explants. Higher levels of TNF-α were seen conditioned medium from aPL-treated placental explant cultures. aPLs appear to induce endoplasmic reticulum stress in the syncytiotrophoblast in a manner that involved caspase 8 and TNF-α. To avoid accumulation of the associated misfolded proteins and MLKL, the syncytiotrophoblast exports these potentially dangerous proteins in EVs. It is likely that the dangerous proteins that are loaded into placental EVs in preeclampsia contribute to dysfunction of the maternal cells.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies

et al. 2020

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“…Ptx treatment was also shown to cause an induced prominence of PGCCs [ [13] and data not shown]. A shared pathway downstream of low oxygen tension and Ptx treatment is the endoplasmic reticulum (ER) stress-mediated UPR pathway [18,[37][38][39][40][41][42][43][44]. We thus hypothesized that UPR activation may result in cancer cell fusion enhancement and PGCCs formation.…”

Section: Discussionmentioning

confidence: 99%

“…Together, these results tend to confirm the role of UPR, probably through the activation of the three UPR sensors ATF6, IRE1α and PERK, in ovarian cancer cell-cell fusion. PERK is known to promote eIF2α phosphorylation, and thus the translation of ATF4 [review at [18]]. ATF4 is one of the transcription factor family members of cAMP response element binding (CREB) and was shown to promote expression of fusogen, syncytin 2, and thus cell fusion in a choriocarcinoma cell line [29].…”

Section: Figure 5: Ers Induction Enhances Cell Fusion In Ovarian Cancmentioning

confidence: 99%

“…These conditions are capable of triggering the endoplasmic reticulum stress (ERS) response or unfolded protein response (UPR) which is essential for cellular adaptation to stressful situations [17]. In homeostatic conditions, the three UPR-associated proteins, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6), remain inactive because of their binding with Glucose-regulated protein 78 (GRP78) [review at [18]]. Under ERS conditions, unfolded proteins accumulate in the ER lumen, promoting the recruitment of chaperones to enable their correct folding.…”

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confidence: 99%

“…Among these chaperones, GRP78 leaves the complexes formed with the UPR-associated proteins and induces the UPR activation [19]. This gives rise to a general decrease of protein, by contrast with increased expression of chaperones and ER-associated protein degradationrelated proteins (ERAD) and autophagy activation [review at [18]]. The overexpression of GRP78 serves as UPR activation marker together with C/EBP homologous protein (CHOP) [20].…”

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confidence: 99%

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Linking endoplasmic reticulum stress to polyploidy in ovarian cancer cells

Yart

Bastida-Ruiz

Wuillemin

et al. 2020

Preprint

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Polyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors and have the ability to survive to antimitotic drugs. Their appearance can result from paclitaxel treatment or hypoxia, two conditions known to induce unfolded protein response (UPR) activation. PGCCs produced under hypoxia may be formed by cell fusion and can contribute by bursting and budding to the generation of cancer stem-like cells which have a more aggressive phenotype than the parental cells. Despite the fact that PGCCs may contribute to tumor maintenance and recurrence, they were poorly studied. Here, we confirmed that PGCCs could derive, at least in part, from cell fusion. We also observed that PGCCs nuclei were able to fuse. The resulting cells were able to proliferate by mitosis and were more invasive than the parental cancer cells. Using two different ovarian cancer cell lines (COV318 and SKOV3), we showed that UPR activation with chemical inducers increased cell fusion and PGCCs appearance. Down-regulation of the UPR-associated protein PERK expression partially reversed the UPR-induced PGCCs formation, suggesting that the PERK arm of the UPR is involved in ovarian PGCCs onset. Keywords: ER stress; unfolded protein response; ovarian cancer; PGCC; cell fusion; nuclei fusion; invasion large cells containing several copies of DNA and positive for cancer stem cell markers [10]. Interestingly, the presence of PGCCs in ovarian cancer has been reported preferentially at late disease stages and in high pathological grades [10]. We previously showed that primary EOC cells isolated from malignant ascites were able to spontaneously form PGCCs in culture [11]. However, the origin of PGCCs is controversial since both fusion or endoreplication processes could give rise to them [8,9,12]. Zhang et al., demonstrated that in SKOV3, an EOC cell line established from ascites, the formation of PGCCs was at least partially due to cell fusion events [9]. In the study conducted by Zhang et al., the PGCCs derived from EOC cells had striking properties such as different cell cycle regulation and division profile, changing their daughter generation mechanism from mitosis to budding, which confer these cells the resistance to cytotoxic chemotherapy treatments [9]. Additionally, it was found that hypoxia increased PGCCs formation [9,[13][14][15], but other conditions such as chemotherapy could also favor their production [13].The tumor environment is known to be hypoxic and hypoglycemic due to the low irrigation caused by the fast and erroneous angiogenesis that tumor mass undergo [reviewed at [16]]. These conditions are capable of triggering the endoplasmic reticulum stress (ERS) response or unfolded protein response (UPR) which is essential for cellular adaptation to stressful situations [17]. In homeostatic conditions, the three UPR-associated proteins, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6), remain inactive because of their binding with Gl...

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Integrated proteome and acetylome analyses unveil protein features of gestational diabetes mellitus and preeclampsia

Tang

et al. 2022

Proteomics

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Gestational diabetes mellitus (GDM) and preeclampsia (PE) are associated with maternal and infant health. Although the pathogenesis of PE and GDM remains controversial, oxidative stress is involved in the underlying pathology of GDM and PE. Protein lysine acetylation (Kac) plays an important regulatory role in biological processes. There is little data regarding the association of the maternal acetylome with GDM and PE. This study aimed to assess the potential value of the proteome and acetylome for GDM and PE. In our study, we included placental tissues from healthy individuals (n = 6), GDM patients (n = 6), and PE patients (n = 6) to perform 4D-label free quantification proteomics analysis and PRM analysis. We identified 22 significantly regulated proteins and 192 significantly regulated acetylated proteins between the GDM and PE groups. Furthermore, 192 significantly regulated acetylated proteins were mainly enriched in endoplasmic reticulum stress (ERS) and ferroptosis pathways. Seventeen acetylated sites in these two pathways were verified by PRM analysis. Our comprehensive analysis revealed key features of GDM/PE-significantly regulated acetylated proteins in the placentas from GDM and PE. The results of signaling pathway analysis focused on ERS and ferroptosis. These findings may help

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Endoplasmic reticulum stress responses in placentation - A true balancing act

Cited by 36 publications

References 72 publications

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies

Linking endoplasmic reticulum stress to polyploidy in ovarian cancer cells

Integrated proteome and acetylome analyses unveil protein features of gestational diabetes mellitus and preeclampsia

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