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Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma [HepG2]

ABSTRACT: Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96793 | GEO | 2017/03/19

SECONDARY ACCESSION(S): PRJNA379714

REPOSITORIES: GEO

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Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma [Hep3B]

Project description:Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.

2017-03-19 | GSE96792 | GEO

Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma [SNU761]

2017-03-19 | GSE96795 | GEO

Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma [Huh7]

2017-03-19 | GSE96794 | GEO

Treatment of Neuroblastoma Cells with Inhibitors of Protein Disulfide Isomerase Upregulates NQO1 Activity

Project description:Protein disulfide isomerase (PDI) is associated with many diseases including neurodegenerative disorders like Alzheimer’s disease and, hence, is considered a promising drug target. This study employs the two PDI inhibitors securinine and 16F16 in order to interrogate the role of PDI in the neurological disease and presents a novel link between PDI inhibition and NQO1 activity Microarrays were used to analyze the global change in gene expression as a result of PDI inhibition in the human neuroblastoma cell line SH-SY5Y

2020-12-31 | GSE153259 | GEO

Expression data from SH-SY5Y neuroblastoma cells treated with the protein disulfide isomerase inhibitor origamicin

Project description:Protein disulfide isomerase (PDI) is associated with many diseases including neurodegenerative disorders like Alzheimer’s disease and, hence, is considered a promising drug target. In this study, we investigate the abscisic acid (ABA)-derived PDI inhibitor origamicin for its neuropharmacological potential. We used microarrays to analyze the global change in gene expression as a result of PDI inhibition in the human neuroblastoma cell line SH-SY5Y

2020-12-31 | GSE129171 | GEO

The protein disulfide isomerase AGR2 is essential for the production of intestinal mucus

Project description:Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells, but the function of AGR2 has been obscure. Here we show that AGR2 is expressed in the ER of secretory cells and is essential for in vivo production of intestinal mucin, a large cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, consistent with a direct role for AGR2 in mucin processing. Despite a complete absence of intestinal mucin, mice lacking AGR2 appeared healthy but were highly susceptible to dextran sodium sulfate-induced experimental colitis, indicating a critical role for AGR2 in protection from environmental insults. We conclude that AGR2 is a unique member of the PDI family that has a specialized and non-redundant role in intestinal mucus production. Keywords: small intestine and colon gene expression profiles for Agr2-/- and littermate control mice DNA miocroarrays were used to analyze small intenstine and colon mRNA expression of AGR2 KO and littermate control mice. The experiment incorporated a 1 color design and used Agilent arrays that contained roughly 44,00 60mer probes that provide complete coverage of the mouse genome. 12 arrays were hybridized and represent 8 small intestine samples ( 4 each KO and WT) and 4 colon samples (2 each KO and WT)

2010-05-19 | E-GEOD-12503 | biostudies-arrayexpress

The protein disulfide isomerase AGR2 is essential for the production of intestinal mucus

2009-05-15 | GSE12503 | GEO

Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

Project description:Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

| PRJNA379711 | ENA

Sorafenib resistance related circRNAs

Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.

2020-07-25 | GSE101850 | GEO

Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

Project description:Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitise resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signalling, prevents this Warburg shift. p53 is necessary and sufficient for the sorafenib-sensitizing effect of nutrient restriction and crucial for improvement of sorafenib efficacy through intermittent fasting (IF) in an orthotopic HCC mouse model. Together, our data indicate IF and sorafenib as clinically actionable, rational combination therapy for HCC with intact p53 signalling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies with the goal of improving therapy response in advanced-stage, and possibly even early-stage, HCC.

2022-02-16 | PXD022723 | Pride

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