scholarly journals iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 879 ◽  
Author(s):  
Ming ◽  
Zhu ◽  
Tuma-Kellner ◽  
Ganzha ◽  
Liebisch ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Fibrosis ◽  
Bile Acids ◽  
Cytokeratin 19 ◽  
Deficient Diet ◽  
Unfolded Protein ◽  
Hepatic Bile Acids ◽  
Calcium Independent Phospholipase A2 ◽  
Protein Response ◽  
Ductular Proliferation

Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β−/− mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). Methods: Female WT (wild-type) and iPla2β−/− mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. Results: MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. Conclusion: iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.

TXNIP links anticipatory unfolded protein response to estrogen reprogramming glucose metabolism in breast cancer cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Yuanzhong Wang ◽  
Shiuan Chen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To adapt the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory unfolded protein response (UPR) and subsequently repressing TXNIP expression. By using two widely used ER+ breast cancer cell lines MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

scholarly journals Long non-coding RNA FAM83H-AS1 induced by adipose-derived stem cells promotes breast and pancreatic cancer cell proliferation and migration

2020 ◽  
Author(s):  
Jianing Tang ◽  
Qiuxia Cui ◽  
Dan Zhang ◽  
Xing Liao ◽  
Yan Gong ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Adipose Derived Stem Cells ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Protein Response ◽  
Proliferation And Migration

Abstract Background Stromal cells recruited to the tumor microenvironment and long non-coding RNAs (lncRNAs) in the tumor cells regulate cancer progression. However, their relationship is largely unknown. Methods In the current study, we identified the effects of lncRNA FAM83H-AS1, induced by adipose-derived stem cells (ADSCs) during tumor development, and explored the underlying mechanisms using a coculture cell model. Adipose tissues were obtained from healthy female donors, the expression of stromal markers on cell surface of expanded ADSCs were confirmed using immunofluorescence analysis. The breast and pancreatic cancer cells were cultured with or without ADSCs using 24-well transwell chamber systems with 8.0 µm pore size. Results Our results showed that FAM83H-AS1 was upregulated in breast and pancreatic cancers and associated with poor prognosis. ADSCs further induced FAM83H-AS1 and increased tumor cell proliferation via promoting G1/S transition through cyclin D1, CDK4 and CDK6. Wound healing, modified Boyden chamber and immunoblotting assays demonstrated that ADSCs induced epithelial-mesenchymal transition and migration of breast and pancreatic cancer cells in a FAM83H-AS1-dependent manner. And ADSC-induced FAM83H-AS1 increased unfolded protein response through AKT/XBP1 pathway. Conclusion In conclusion, our results indicated that ADSCs promoted breast and pancreatic cancer development via inducing cell proliferation and migration, as well as unfolded protein response through FAM83H-AS1.

scholarly journals Pentoxifylline Attenuates Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis by Suppressing TNF-αExpression and Endoplasmic Reticulum Stress

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Min Kyung Chae ◽  
Sang Gyu Park ◽  
Sun-Ok Song ◽  
Eun Seok Kang ◽  
Bong Soo Cha ◽  
...  
Keyword(s):  
Er Stress ◽  
Deficient Diet ◽  
Group Iii ◽  
Unfolded Protein ◽  
Sd Rats ◽  
Group I ◽  
Hep3b Cells ◽  
Protein Response

Background. Pentoxifylline (PTX) anti-TNF properties are known to exert hepatoprotective effects in various liver injury models. The aim of this study was to investigate whether PTX has beneficial roles in the development of methionine- and choline-deficient-(MCD-) diet-induced NAFLD SD ratsin vivoand TNF-α-induced Hep3B cellsin vitro.Methods. SD Rats were classified according to diet (chow or MCD diet) and treatment (normal saline or PTX injection) over a period of 4 weeks: group I (chow + saline,n=4), group II (chow + PTX), group III (MCD + saline), and group IV (MCD + PTX). Hep3B cells were treated with 100 ng/ml TNF-α(24 h) in the absence or presence of PTX (1 mM).Results. PTX attenuated MCD-diet-induced serum ALT levels and hepatic steatosis. In real-time PCR and western blotting analysis, PTX decreased MCD-diet-induced TNF-alpha mRNA expression and proapoptotic unfolded protein response by ER stress (GRP78, p-eIF2, ATF4, IRE1α, CHOP, and p-JNK activation)in vivo. PTX (1 mM) reduced TNF-α-induced activation of GRP78, p-eIF2, ATF4, IRE1α, and CHOPin vitro.Conclusion. PTX has beneficial roles in the development of MCD-diet-induced steatohepatitis through partial suppression of TNF-αand ER stress.

scholarly journals Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha

2020 ◽  
Vol 21 (10) ◽  
pp. 3636 ◽  
Author(s):  
Ya-Ling Yang ◽  
Feng-Sheng Wang ◽  
Hung-Yu Lin ◽  
Ying-Hsien Huang
Keyword(s):  
Liver Fibrosis ◽  
Unfolded Protein Response ◽  
Luciferase Reporter ◽  
Heat Shock Protein 60 ◽  
Unfolded Protein ◽  
Duct Ligation ◽  
Phosphoinositide 3 Kinase ◽  
Human Liver Cirrhosis ◽  
Protein Response

Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1β), fibrogenesis (TGF-β1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPRmt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3′ untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury.

scholarly journals The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4443
Author(s):  
Ankit Patel ◽  
Masanori Oshi ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
Itaru Endo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Unfolded Protein Response ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Immune Cell ◽  
Histological Grade ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

scholarly journals TRiC activates the unfolded protein response and protects starved stem cells by modulating energy and lipid metabolism during planarian regeneration

2019 ◽  
Author(s):  
Óscar Gutiérrez-Gutiérrez ◽  
Daniel A. Felix ◽  
Alessandra Salvetti ◽  
Anne Thems ◽  
Stefan Pietsch ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Lipid Metabolism ◽  
Unfolded Protein Response ◽  
Stem Cell Proliferation ◽  
Unfolded Protein ◽  
Cell Genome ◽  
The Unfolded Protein Response ◽  
Protein Response

SummaryFasting protects stem cells and increases stem cell functionality through mechanisms which are not fully understood. Planarians are not only able to regenerate their bodies, but also to stand long periods of starvation by shrinking in size. This adaptation is possible because of a large population of adult stem cells which indefinitely self-renew even under starved conditions and thus confer planarians with immortality. How starved planarians are able to maintain healthy stem cells and to fuel stem cell proliferation allowing regeneration is unknown. Here we found the TCP-1 ring complex (TRiC) to be upregulated in starved stem cells. Down-regulation of TRiC impairs planarian regenerative response by inducing stem cell genome instability, mitotic defects and stem cell death which translates into stem cell exhaustion. This regulation is specific of starvation since feeding planarians prevents the phenotype. Importantly we found that TRiC activates the unfolded protein response (UPR) which allows a convergent regulation of cellular energy and lipid metabolism in starved planarians thus permitting the high energy demanding regenerative mitotic response. We identified a novel mechanism through which starvation protects the somatic stem cell genome allowing for unlimited stem cell proliferation and regeneration.

Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation

2010 ◽  
Vol 391 (1) ◽  
pp. 778-782 ◽  
Author(s):  
Bao-Qin Liu ◽  
Yan-Yan Gao ◽  
Xiao-Fang Niu ◽  
Ji-Sheng Xie ◽  
Xin Meng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Unfolded Protein Response ◽  
K562 Cell ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals The LncRNA MIR503HG/miR-224-5p/TUSC3 Signaling Cascade Suppresses Gastric Cancer Development via Modulating ATF6 Branch of Unfolded Protein Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Han Lin ◽  
Jinge Wang ◽  
Tong Wang ◽  
Jiaming Wu ◽  
Peng Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Blue Staining ◽  
Signaling Cascade ◽  
Mesenchymal Transition ◽  
Unfolded Protein ◽  
Protein Response

BackgroundUnfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis.MethodsThe bioinformatics analysis was performed to examine the expression status of cancer associated genes in patients with stomach adenocarcinoma (STAD) and predict the targeting sites of miR-224-5p with LncRNA MIR503HG and TUSC3. Genes expressions were quantified by Real-Time qPCR, Western Blot and immunohistochemistry (IHC). Cell proliferation, viability, apoptosis and mobility were evaluated by MTT assay, trypan blue staining assay, flow cytometer and transwell assay, respectively. The binding sites were validated by dual-luciferase reporter gene system assay.ResultsLncRNA MIR503HG and TUSC3 were downregulated, but miR-224-5p was upregulated in GC tissues and cells, in contrast with their normal counterparts. Further gain- and loss-of-function experiments validated that the malignant phenotypes in GC cells, including cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and tumorigenesis, were negatively regulated by LncRNA MIR503HG. Mechanistically, LncRNA MIR503HG upregulated TUSC3 in GC cells through sponging miR-224-5p, resulting in the repression of GC progression. Finally, we validated that knock-down of ATF6, but not other two branches of UPR (PERK1 and IRE1), partially rescued cell proliferation and EMT in the GC cells with LncRNA MIR503HG overexpression.ConclusionsTargeting the LncRNA MIR503HG/miR-224-5p/TUSC3 signaling cascade suppressed ATF6-mediated UPR, resulting in the blockage of GC development.

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