Comparison between drugs- and unfolded proteins-induced responses reveals early induction of components of an ER-resident multimeric complex binding unfolded proteins
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108346 | GEO | 2018/02/16
REPOSITORIES: GEO
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Project description:The stress sensors ATF6, IRE1 and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to re-establish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, sugars or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized. Here, we compared gene and protein expression profiles in cells challenged with ER stress-inducing drugs or expressing model polypeptides. Drugs titration to limit up-regulation of the endogenous ER stress reporters BiP/HSPA5 and HERP/HERPUD1 to levels comparable to luminal accumulation of unfolded proteins substantially reduced the amplitude of transcriptional and translational responses. Nevertheless, these remained pleiotropic and failed to recapitulate responses to ER load with unfolded proteins, which induced a limited subset of genes participating in a chaperone complex that binds unfolded chains.
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Project description:Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.
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Project description:We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.
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Project description:Transcriptional profiling of K562-r comparing control untreated human leukemia cells with human leukemia cells treated with AMN107 and ATO individually or combined.Four timepoints included are 3h,12h,24h,48h, covering the whole time window of K562-r cells responsing to the drug treatment.At the combination of 1.5uM ATO and 8uM AMN107, K562-r cells have the most significant coordinated effects (the apoptosis rate at 72h was 56.41% compared to 12.23% in ATO alone and 29.8% in AMN107 alone.). We studied gene expression series in K562-r cells with or without drug treatments by cDNA microarray analysis. Many genes involved in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1 and TXNDC12, were highly up-regulated within 12 h of co-treatment, suggesting that the combination of ATO with AMN107 induced an ER stress response leading to apoptosis later on. Other ER-stress markers like the JNK pathway, which bridges the ER-stress and apoptosis, have been activated. Knock down the initiator of JNK partially alleviate the effects of apoptosis (p<0.05). Co-administering AMN107 and arsenic trioxide, inducing apoptosis via the ER-stress, indicates a novel therapy alternative for the imatinib induced secondary resistance.
2010-12-30 | GSE24946 | GEO
Project description:Transcriptional profiling of K562-r comparing control untreated human leukemia cells with human leukemia cells treated with AMN107 and ATO individually or combined.Four timepoints included are 3h,12h,24h,48h, covering the whole time window of K562-r cells responsing to the drug treatment.At the combination of 1.5uM ATO and 8uM AMN107, K562-r cells have the most significant coordinated effects (the apoptosis rate at 72h was 56.41% compared to 12.23% in ATO alone and 29.8% in AMN107 alone.). We studied gene expression series in K562-r cells with or without drug treatments by cDNA microarray analysis. Many genes involved in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1 and TXNDC12, were highly up-regulated within 12 h of co-treatment, suggesting that the combination of ATO with AMN107 induced an ER stress response leading to apoptosis later on. Other ER-stress markers like the JNK pathway, which bridges the ER-stress and apoptosis, have been activated. Knock down the initiator of JNK partially alleviate the effects of apoptosis (p<0.05). Co-administering AMN107 and arsenic trioxide, inducing apoptosis via the ER-stress, indicates a novel therapy alternative for the imatinib induced secondary resistance. 17-condition experiment, untreated K562-r vs. Drug-treated K562-r cells, including 4 time points, for each point the untreated and 1.5uM ATO treated,8uM AMN107 treated and both 1.5uM ATO and 8uM AMN107 treated, independently grown and harvested. One replicate per array. Untreated K562-r_0h used to counteracting the background.
2010-12-30 | E-GEOD-24946 | biostudies-arrayexpress
Project description:2',3,5-Trimethoxychalcone (MC-23) triggers apoptosis independently of p53 in MiaPaCa2 cells. To understand the mechanism of action of MC-23, we analysed the gene expression profiles in MiaPaCa2 cells treated with 10 μM MC-23 for 6, 12, or 24 h using the Agilent human 44K oligonucleotide V2 microarray. Out of the 34,127 genes in the array, MC-23 upregulated ~3% and downregulated. Notably, a large number of genes associated with apoptosis (such as BAX, BAK), chaperones (such as HSPA1/HSP70, HSPA5/GRP78/BiP), and the unfolded protein response (such as IRE1α, CHOP/DDIT3/GADD153, XBP1, ATF4, ATF6) were highly up-regulated by MC-23 treatment, suggesting that ER stress is associated with MC-23-induced apoptosis.
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Project description:Analysis of gene expression can be challenging, especially if it involves genetically diverse populations that exhibit high variation in their individual expression profile. Despite this variation though, it is conceivable that in the same individuals a high degree of coordination is maintained between transcripts that belong to the same signaling modules and are associated with related biological functions. To explore this further, we calculated the correlation in the expression levels between each of ATF4, CHOP (DDIT3), GRP94, DNAJB9 (ERdj4), DNAJ3C (p58IPK) and HSPA5 (BiP/GRP78) with the whole transcriptome in primary fibroblasts from deer mice following induction of endoplasmic reticulum (ER) stress. Since these genes are associated with different transducers of the unfolded protein response (UPR) we postulated that their profile, in terms of correlation of transcripts, reflects distinct UPR branches engaged and therefore different biological processes. Standard gene ontology analysis was able to predict major functions associated with the corresponding transcript, and of the UPR arm related to that, namely regulation of the apoptotic response by ATF4 (PERK arm) and the ER stress associated degradation for GRP94 (IRE1). BiP, being a global regulator of the UPR, was associated with activation of ER stress in a rather global manner. Pairwise comparison in the correlation coefficients for these genes’ associated transcriptome showed the relevance of selected genes in terms of expression profiles.
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Project description:Zinc is an essential trace element, and impaired zinc homeostasis is implicated in the pathogenesis of various human diseases. However, the mechanisms cells use to respond to zinc deficiency are poorly understood. We previously reported that amyotrophic lateral sclerosis (ALS)-linked pathogenic mutants of SOD1 cause chronic ER stress through specific interactions with Derlin-1, which is a component of the ER-associated degradation machinery. Moreover, we recently demonstrated that this interaction is common to ALS-linked SOD1 mutants, and SOD1WT comprises a masked Derlin-1-binding region. We found that under serum starved and zinc-deficient conditions, SOD1WT adopts a mutant-like conformation that exposes the Derlin-1-binding region, suggesting that SOD1-Derlin-1 interaction may contribute to induce ER stress under these conditions. Using RNA microarrays, we revealed that the zinc depletion and serum starvation induce the expression of the unfolded protein response (UPR) target genes, including HSPA5/BiP, SEL1L, DNAJC3/p58, and ARMET. We conclude that SOD1 has a novel function as a molecular switch that activates the ER stress response under zinc-deficient conditions HeLa cells were treated with 8M-BM-5M TPEN for 9h or exposured to 36h of serum starvation with or without 30M-BM-5M zinc.Then the total RNA was isolated from cells using the Isogen reagent (Wako) following the manufacturer's recommendations.
2013-08-09 | E-GEOD-49657 | biostudies-arrayexpress
Project description:2',3,5-Trimethoxychalcone (MC-23) triggers apoptosis independently of p53 in MiaPaCa2 cells. To understand the mechanism of action of MC-23, we analysed the gene expression profiles in MiaPaCa2 cells treated with 10 M-NM-<M MC-23 for 6, 12, or 24 h using the Agilent human 44K oligonucleotide V2 microarray. Out of the 34,127 genes in the array, MC-23 upregulated ~3% and downregulated. Notably, a large number of genes associated with apoptosis (such as BAX, BAK), chaperones (such as HSPA1/HSP70, HSPA5/GRP78/BiP), and the unfolded protein response (such as IRE1M-NM-1, CHOP/DDIT3/GADD153, XBP1, ATF4, ATF6) were highly up-regulated by MC-23 treatment, suggesting that ER stress is associated with MC-23-induced apoptosis. Global gene expression profile was measured at 6, 12, and 24 hours after exposure to doses of 10 M-NM-<M MC-23 in MiaPaCa2 cells. Three independent experiments were performed at each time using different experiments.
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Project description:We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. Profiling of 3 human melanoma cell lines (SKMel28, Mel501, A375) treated with HA15 at 10 uM or with DMSO was performed using whole genome human microarrays. Cells were incubated with DMSO or HA15 for 6h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment, total of 6 samples.
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