Targeting the IRE1α/XBP1 endoplasmic reticulum stress response pathway in ARID1Amutant ovarian cancers
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PROVIDER: PRJNA748370 | ENA |
REPOSITORIES: ENA
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Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157117 | GEO
Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157116 | GEO
Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.
2020-05-16 | GSE131404 | GEO
Project description:xenograft, patientderived xenograft and the genetic Arid1aflox/flox/Pik3caH1047R mouse models. Finally, B-I09 synergizes with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies reveal a promising therapeutic strategy for ARID1A-mutant OCCCs and define the IRE1?-XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs. Our findings indicate that pharmacological inhibition of the IRE1?-XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.
2021-08-10 | GSE180468 | GEO
Project description:Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods: We evaluated 34 human liver explants. Cohorts included: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results: Metascape pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and could be targeted to treat pediatric CLD.
2022-06-23 | GSE206364 | GEO
Project description:Tumors evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intratumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer (OvCa), an aggressive malignancy refractory to standard treatments and current immunotherapies, induces Endoplasmic Reticulum (ER) stress and activation of the IRE1α-XBP1 arm of the Unfolded Protein Response (UPR)10,11 in T cells to control their mitochondrial respiration and anti-tumor function. XBP1 upregulation in T cells isolated from human OvCa specimens was associated with decreased intratumoral T cell infiltration and reduced IFNG mRNA expression. Malignant ascites fluid obtained from OvCa patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to IRE1α/XBP1-driven suppression of mitochondrial activity and IFN- production. Mechanistically, XBP1 induction limited the influx of glutamine necessary to sustain T cell mitochondrial respiration under glucose-deprived conditions by regulating the abundance of glutamine carriers. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to OvCa ascites. XBP1-deficient T cells in the metastatic OvCa milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, OvCa-bearing mice lacking XBP1 selectively in T cells demonstrated superior anti-tumor immunity, delayed malignant progression and increased overall survival. Therefore, controlling ER stress or targeting IRE1α-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.
2018-10-18 | GSE118430 | GEO
Project description:Transcriptional profiling of INS1 cells expressing either WT IRE1α, I642G IRE1α, N906A IRE1α, or spliced XBP1 comparing 1μg/mL dox and 5μM 1NMPP1 treated vs control.
2014-12-22 | GSE17148 | GEO
Project description:Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARγ and C/EBPα. Here we demonstrate that the IRE1α-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1α knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPβ, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1α is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1α-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis.
2009-04-25 | GSE15771 | GEO
Project description:CARM1 determines endoplasmic reticulum stress response by controlling XBP1 in ovarian cancer
| PRJNA660169 | ENA
Project description:We set out to determine the role of the IRE1/XBP1 pathway, the most ancient and highly conserved endoplasmic reticulum (ER) stress-sensing pathway of the unfolded protein response (UPR), in Schmid metaphyseal chondrodysplasia (MCDS). RNA derived from hypertrophic zones microdissected from growth plates of wildtype mice, mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), mice carrying a COL10A1 pN617K mutation (ColXN617K), and compound mutants (C/X) was analyzed by whole genome microarray analysis. 1633 probes were differentially expressed between ColXN617K and wildtype, 215 probes were differentially expressed between Xbp1Cart?Ex2 and wildtype, and 1337 probes were differentially expressed between C/X and wildtype. 885 probes were differentially expressed between ColXN617K and wildtype but not Xbp1Cart?Ex2 and wildtype or C/X and wildtype, thus representing the XBP1-dependent response to hypertrophic chondrocyte ER stress. 688 probes were differentially expressed between ColXN617K and wildtype and between C/X and wildtype but not Xbp1Cart?Ex2 and wildtype, thus representing the XBP1-independent response to hypertrophic chondrocyte ER stress. Results were validated by qPCR. Entire growth plate hypertrophic zones were microdissected from one tibia from each of three 2-week old wildtype mice, three 2-week old mice carrying a COL10A1 p.N617K mutation (ColXN617K), three 2-week old mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), and three 2-week old mice resulting from a cross between ColXN617K and Xbp1Cart?Ex2 (C/X).
2015-08-21 | E-GEOD-72261 | biostudies-arrayexpress