Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells.
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ABSTRACT:
SUBMITTER: Yoon S
PROVIDER: S-EPMC8424138 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor cells are stressed by unfavorable environmental conditions like hypoxia or starvation. Driven by the resulting cellular stress tumor cells undergo epithelial-mesenchymal transition. Additionally, cellular stress is accompanied by endoplasmic reticulum-stress which induces an unfolded protein response. It is unknown if epithelial-mesenchymal transition and endoplasmic reticulum-stress are occurring as independent parallel events or if an interrelationship exists between both of them. Here, we show that in colorectal cancer cells endoplasmic reticulum-stress depends on the induction of ZEB-1, which is a main factor of epithelial-mesenchymal transition. In the absence of ZEB-1 colorectal cancer cells cannot mount endoplasmic reticulum-stress as a reaction on cellular stress situations like hypoxia or starvation. Thus, our data suggest that there is a hierarchy in the development of cellular stress which starts with the presence of environmental stress that induces epithelial-mesenchymal transition which allows finally endoplasmic reticulum-stress. This finding highlights the central role of epithelial-mesenchymal transition during the process of tumorigenesis as epithelial-mesenchymal transition is also associated with chemoresistance and cancer stemness. Consequently, endoplasmic reticulum-stress might be a well suited target for chemotherapy of colorectal cancers.
| S-EPMC3909180 | biostudies-literature
Project description:BackgroundEpithelial-mesenchymal transition (EMT) is a key process in the onset and development of idiopathic pulmonary fibrosis (IPF) with unclear mechanisms. Our previous studies found that bleomycin and tunicamycin could induce ER stress and consequently trigger EMT accompanying with IL-32 overexpression. This study was aimed to investigate the effects of IL-32 on EMT and ER stress to elucidate the pathogenesis of IPF.MethodsHuman lung adenocarcinoma A549 cells were treated with recombinant human (rh)IL-32, IL-32 siRNA and EMT inducer tunicamycin, or 4-phenylbutyric acid (4-PBA), respectively. Then the cell morphology was observed and the expression of ER-related markers and EMT-related markers were detected by RT-qPCR or western blotting.ResultsStimulation of A549 cells with rhIL-32 led to a morphological change from a pebble-like shape to an elongated shape in a portion of the cells, accompanied by down regulated expression of the epithelial cell marker E-cadherin and up regulated expression of the mesenchymal cell markers N-cadherin, Vimentin, and Zeb-1. However, these rhIL-32 induced changes were inhibited by the ER stress inhibitor 4-PBA. Suppression of IL-32 expression with siRNA inhibited TM-induced EMT. Further stimulation of the A549 cells with rhIL-32 demonstrated an increase in the expression of GRP78, although this increase was also inhibited by 4-PBA.ConclusionsThese results suggest that IL-32 induces EMT in A549 cells by triggering ER stress, and IL-32 may be a novel marker for IPF.
| S-EPMC7585222 | biostudies-literature
Project description:Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and ?-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, ?-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible cross-talk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis.
| S-EPMC3162456 | biostudies-literature
Project description:The mechanism underlying the loss of normal liver tissues in liver cirrhosis, mainly hepatocytes, is not well-characterized. Endoplasmic reticulum (ER) stress-induced cell death has emerged as a potential mechanism for chronic liver diseases. We have previously demonstrated that cyclooxygenase-2 (COX-2) is closely related to the progress of liver cirrhosis. In this study, we aimed to verify whether hepatocytes COX-2 deficiency could protect liver injury via inducing ER stress in liver cirrhosis.
2024-04-28 | GSE183888 | GEO
Project description:Endoplasmic reticulum (ER) stress has been implicated in alveolar epithelial type II (AT2) cell apoptosis in idiopathic pulmonary fibrosis. We hypothesized that ER stress (either chemically induced or due to accumulation of misfolded proteins) is also associated with epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs). ER stress inducers, thapsigargin (TG) or tunicamycin (TN), increased expression of ER chaperone, Grp78, and spliced X-box binding protein 1, decreased epithelial markers, E-cadherin and zonula occludens-1 (ZO-1), increased the myofibroblast marker, ?-smooth muscle actin (?-SMA), and induced fibroblast-like morphology in both primary AECs and the AT2 cell line, RLE-6TN, consistent with EMT. Overexpression of the surfactant protein (SP)-C BRICHOS mutant SP-C(?Exon4) in A549 cells increased Grp78 and ?-SMA and disrupted ZO-1 distribution, and, in primary AECs, SP-C(?Exon4) induced fibroblastic-like morphology, decreased ZO-1 and E-cadherin and increased ?-SMA, mechanistically linking ER stress associated with mutant SP to fibrosis through EMT. Whereas EMT was evident at lower concentrations of TG or TN, higher concentrations caused apoptosis. The Src inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4]pyramidine) (PP2), abrogated EMT associated with TN or TG in primary AECs, whereas overexpression of SP-C(?Exon4) increased Src phosphorylation, suggesting a common mechanism. Furthermore, increased Grp78 immunoreactivity was observed in AT2 cells of mice after bleomycin injury, supporting a role for ER stress in epithelial abnormalities in fibrosis in vivo. These results demonstrate that ER stress induces EMT in AECs, at least in part through Src-dependent pathways, suggesting a novel role for ER stress in fibroblast accumulation in pulmonary fibrosis.
| S-EPMC3175581 | biostudies-literature
Project description:BackgroundSeveral studies demonstrate that endoplasmic reticulum (ER) stress-mediated epithelial-mesenchymal transition (EMT) is involved in the process of bleomycin (BLM)-induced pulmonary fibrosis. Tauroursodeoxycholic acid (TUDCA), a bile acid with chaperone properties, is an inhibitor of ER stress. This study aimed to investigate the preventive effects of TUDCA on BLM-induced EMT and lung fibrosis.MethodsThe model of lung fibrosis was established by intratracheal injection with a single dose of BLM (3.0 mg/kg). In TUDCA + BLM group, mice were intraperitoneally injected with TUDCA (250 mg/kg) daily.ResultsBLM-induced alveolar septal destruction and inflammatory cell infiltration were alleviated by TUDCA. BLM-induced interstitial collagen deposition, as determined by Sirius Red staining, was attenuated by TUDCA. BLM-induced elevation of pulmonary α-smooth muscle actin (α-SMA) and reduction of pulmonary E-cadherin were attenuated by TUDCA. BLM-induced pulmonary Smad2/3 phosphorylation was suppressed by TUDCA. BLM-induced elevation of Ki67 and PCNA was inhibited by TUDCA in mice lungs. In addition, BLM-induced elevation of HO-1 (heme oxygenase-1) and 3-NT (3-nitrotyrosine) was alleviated by TUDCA. Finally, BLM-induced upregulation of pulmonary GRP78 and CHOP was attenuated by TUDCA.ConclusionsThese results provide evidence that TUDCA pretreatment inhibits Smad2/3-medited EMT and subsequent lung fibrosis partially through suppressing BLM-induced ER stress and oxidative stress.
| S-EPMC8097922 | biostudies-literature
Project description:The present study aimed to determine whether isorhamnetin (Isor), a natural antioxidant polyphenol, has antifibrotic effects in a murine model of bleomycin?induced pulmonary fibrosis. A C57 mouse model of pulmonary fibrosis was established by intraperitoneal injection of a single dose of bleomycin (3.5 U/kg), and then Isor (10 and 30 mg/kg) was administered intragastrically. The level of fibrosis was assessed by hematoxylin and eosin and Sirius red staining. ??smooth muscle actin and type I collagen levels in lung tissues were determined by western blotting and immunohistochemistry (IHC). Epithelial?mesenchymal transition (EMT), endoplasmic reticulum stress (ERS) and related signaling pathways were examined by western blotting and IHC. In vitro, human bronchial epithelial cells (HBECs) and A549 cells were treated with transforming growth factor (TGF)?1 with or without Isor, and collagen deposition and the expression levels of EMT? and ERS?related genes or proteins were analyzed by reverse transcription?quantitative polymerase chain reaction, western blotting, and immunofluorescence. The results demonstrated that Isor inhibited bleomycin?induced collagen deposition, reduced type I collagen and ??SMA expression, and alleviated EMT and ERS in vivo. Furthermore, incubation of HBECs and A549 cells with TGF?1 activated EMT and ERS, and this effect was reversed by Isor. In conclusion, Isor treatment attenuated bleomycin?induced EMT and pulmonary fibrosis and suppressed bleomycin?induced ERS and the activation of PERK signaling.
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Project description:Background: Malignant glioma is a lethal brain tumor that is highly resistant to standard therapy. Our research aims to explore the suppressive effects of nitidine chloride (NC) on gliomas and the mechanisms involved, showing that it is a potential agent for integrative therapy of gliomas. Methods: After glioma cells were treated with NC, several experiments were performed to evaluate NC's antitumor effects. CCK-8 assay was used to detect viability. Transwell and 3-dimensional spheroid invasion assays were used to evaluate motility of glioma in vitro, and the sphere-formation assay showed NC's influence on glioma stem cells. Apoptosis and intracellular reactive oxygen species were measured by means of flow cytometry. Subcellular structures were observed through transmission electron microscopy. Western blot analysis reflected expression of endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) marker proteins. An orthotopic xenograft model was established to investigate the tumor suppressive effects in vivo. Results: Nitidine chloride inhibited glioma cell migration and invasion in vitro, downregulated the EMT proteins, and suppressed sphere formation of glioma stem cells. Furthermore, NC induced persistent ER stress that contributed to apoptosis and reactive oxygen species production. The xenograft model showed that NC effectively restricted glioma growth and invasion in vivo. Furthermore, we confirmed the signaling pathways that ER stress downregulates C/EBP? and slug, as well as inhibition of the AKT/GSK3?/?-catenin axis caused by NC, in U-87 MG. Conclusion: We demonstrated that NC inhibits gliomas in vitro and in vivo by activating ER stress and downregulating EMT, which provides a basis for glioma therapy.
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Project description:Background: The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting in renal tubulointerstitial disease. These pathophysiological responses are collectively described as diabetic tubulopathy (DT). Thus, therapeutic strategies targeting DT hold significant promise for early DKD treatment. Shenkang injection (SKI) has been widely used to treat renal tubulointerstitial fibrosis in patients with chronic kidney disease in China. However, it is still unknown whether SKI can alleviate DT. We designed a series of experiments to investigate the beneficial effects of SKI in DT and the mechanisms that are responsible for its effect on epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress-induced apoptosis in DT. Methods: The modified DKD rat models were induced by uni-nephrectomy, streptozotocin intraperitoneal injection, and a high-fat diet. Following the induction of renal injury, these animals received either SKI, rosiglitazone (ROS), or vehicle, for 42 days. For in vitro research, we exposed NRK-52E cells to high glucose (HG) and 4-phenylbutyric acid (4-PBA) with or without SKI or ROS. Changes in parameters related to renal tubular injury and EMT were analyzed in vivo. Changes in the proportion of apoptotic renal tubular cells and ER stress, and the signaling pathways involved in these changes, were analyzed both in vivo and in vitro. Results: SKI and ROS improved the general condition, the renal morphological appearance and the key biochemical parameters, and attenuated renal injury and EMT in the rat model of DKD. In addition, SKI and ROS alleviated apoptosis, inhibited ER stress, and suppressed PERK-eIF2α-ATF4-CHOP signaling pathway activation both in vivo and in vitro. Notably, our data showed that the regulatory in vitro effects of SKI on PERK-eIF2α-ATF4-CHOP signaling were similar to those of 4-PBA, a specific inhibitor of ER stress. Conclusion: This study confirmed that SKI can alleviate DT in a similar manner as ROS, and SKI achieves this effect by inhibiting EMT and ER stress-induced apoptosis. Our findings thereby provide novel information relating to the clinical value of SKI in the treatment of DT.
| S-EPMC8367077 | biostudies-literature
Project description:Carotid artery stenosis is a leading cause of ischemic stroke, but the underlying mechanism remains unclear. We aimed to determine the molecular mechanisms of carotid plaque progression. We analyzed the molecular and morphometric characteristics of carotid plaque samples obtained from 30 patients who underwent carotid endarterectomy. Additionally, we established a mouse model of carotid atherosclerosis by partially ligating the left common carotid arteries of male ClockΔ19/Δ19 (Clk) and wild-type (WT) C57BL/6J mice fed a high-fat diet. Clk and WT primary mouse aortic endothelial cells (pMAECs) were exposed to disturbed flow (DF) or undisturbed flow (UF) with or without treatment with the IRE-1α inhibitor STF-083010 or the PERK inhibitor GSK2606414. In human carotid artery plaques, CLOCK expression was lower in the lipid-rich necrotic core than in transitional regions, especially in the endothelium. Decreased CLOCK mRNA levels were associated with more extensive stenosis, intraplaque hemorrhage, and complex plaque in human carotid plaques. In mice, the ClockΔ19/Δ19 mutation significantly increased neointima formation and neovascularization but decreased collagen content and lumen area in partially ligated carotid arteries. In addition, ClockΔ19/Δ19 mutants exhibited significantly decreased Cdh5 expression and increased expression of endothelial-mesenchymal transition (EndMT) and endoplasmic reticulum (ER) stress markers in mice with partially ligated carotid arteries and pMAECs exposed to DF. Notably, inhibition of the IRE1α-XBP1 axis abrogated the increased EndMT caused by ClockΔ19/Δ19 mutation and DF in pMAECs. In conclusion, the disruption of CLOCK function aggravates EndMT via the IRE1α-XBP1 axis, contributing to carotid artery stenosis.
| S-EPMC7791501 | biostudies-literature