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The orphan nuclear receptor NR4A1 (Nur77, TR3) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells

ABSTRACT: NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer cells and tumors and exhibits pro-oncogenic activity. Knockdown of NR4A1 by RNA interference (siNR4A1) in Panc1 cells and analysis of the proteome resulted in induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), activating transcription factor-3 (ATF-3) and AFT-6. These effects were accompanied by induction of apoptosis and similar results were observed after treatment of pancreatic cancer cells with the known inactivator of NR4A1, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH). Both siNR4A1 (transfected) and DIM-C-pPhOH also induced reactive oxygen species (ROS) and induction of ROS and ER stress by these agents was attenuated after cotreatment with antioxidants. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1. Knockdown of one of these genes, thioredoxin domain containing 5 (TXNDC5) also resulted in induction of ROS and ER stress demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Inactivation of this receptor by siNR4A1 or DIM-C-pPhOH decreases TXNDC5 resulting in activation of ROS/ER stress and pro-apoptotic pathways and represents a novel pathway for inducing cell death in pancreatic cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46994 | GEO | 2014/04/30

SECONDARY ACCESSION(S): PRJNA203248

REPOSITORIES: GEO

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The orphan nuclear receptor NR4A1 (Nur77, TR3) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells

Project description:NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer cells and tumors and exhibits pro-oncogenic activity. Knockdown of NR4A1 by RNA interference (siNR4A1) in Panc1 cells and analysis of the proteome resulted in induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), activating transcription factor-3 (ATF-3) and AFT-6. These effects were accompanied by induction of apoptosis and similar results were observed after treatment of pancreatic cancer cells with the known inactivator of NR4A1, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH). Both siNR4A1 (transfected) and DIM-C-pPhOH also induced reactive oxygen species (ROS) and induction of ROS and ER stress by these agents was attenuated after cotreatment with antioxidants. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1. Knockdown of one of these genes, thioredoxin domain containing 5 (TXNDC5) also resulted in induction of ROS and ER stress demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Inactivation of this receptor by siNR4A1 or DIM-C-pPhOH decreases TXNDC5 resulting in activation of ROS/ER stress and pro-apoptotic pathways and represents a novel pathway for inducing cell death in pancreatic cancer cells. Two groups of samples are included: 1. siControl; 2. siNR4A1 treatment in PAC1 cell. Transfection of Panc1 cells with siNR4A1 follow by analysis of gene expression by arrays identified ROS metabolism genes regulated by NR4A1.

2014-04-30 | E-GEOD-46994 | biostudies-arrayexpress

Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress

Project description:Background: Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effects of PA on human chemotherapy resistant pancreatic cancer cells. Methods: Gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2 were used, along with a xenograft model of MIA PaCa-2 cells implanted in mice. Apoptosis was assessed by quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP. Differential expression of genes was identified using comparative DNA microarray analysis. Protein levels were determined by immunoblotting. Toxicology studies in vivo were assessed by detecting pathological changes in organs and liver enzyme profiles in plasma. Tumor tissues were analyzed by quantification of apoptotic bodies, qRT-PCR and immunoblotting. Principal Findings: PA induced endoplasmic reticulum (ER) stress in chemotherapy resistant pancreatic cancer cells through activation of heat shock response and unfolded protein response related genes, which further triggered apoptosis. The involvement of ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2M-NM-1. Moreover, 25 mg kgM-bM-^HM-^R1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis, ER stress related genes and proteins expression. Conclusions: Growth inhibition and induction of apoptosis by PA in chemotherapy resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. Pancreatic cancer cell line treated with pachymic acid vs. control (untreated)

2014-12-12 | E-GEOD-64111 | biostudies-arrayexpress

Dietary ligands diindolylmethane and resveratrol result in diverse ERα signaling not seen after E2 and a subset of diindolylmethane mediated signaling needs concurrent AHR activation.

Project description:Inhibitory crosstalk between estrogen receptor alpha (ER alpha ) and aryl hydrocarbon receptor (AHR) regulates 17-estradiol (E2)-dependent breast cancer cell signaling. ER alpha and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,30diindolylmethane (DIM) also activate ER alpha while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and antiinflammatory properties. Studies with genome-wide targets and AHR- and ER alpha-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ER alpha as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ER alpha bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ER alpha site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ER alpha and ER alpha /AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ER alpha dominates with preferential recruitment of AHR to ER alpha target genes.

2023-10-16 | GSE232235 | GEO

Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress

Project description:Background: Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effects of PA on human chemotherapy resistant pancreatic cancer cells. Methods: Gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2 were used, along with a xenograft model of MIA PaCa-2 cells implanted in mice. Apoptosis was assessed by quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP. Differential expression of genes was identified using comparative DNA microarray analysis. Protein levels were determined by immunoblotting. Toxicology studies in vivo were assessed by detecting pathological changes in organs and liver enzyme profiles in plasma. Tumor tissues were analyzed by quantification of apoptotic bodies, qRT-PCR and immunoblotting. Principal Findings: PA induced endoplasmic reticulum (ER) stress in chemotherapy resistant pancreatic cancer cells through activation of heat shock response and unfolded protein response related genes, which further triggered apoptosis. The involvement of ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, 25 mg kg−1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis, ER stress related genes and proteins expression. Conclusions: Growth inhibition and induction of apoptosis by PA in chemotherapy resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo.

2014-12-12 | GSE64111 | GEO

S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells [HG-U133_Plus_2]

Project description:We and others have shown that S100P is highly upregulated during the progression of pancreatic cancer. We used microarrays to look at the target genes regulated by S100P in the pancreatic cancer cell line Panc1. Keywords: Gene overexpression We generated stable cell lines by introducing control vector pcDNA3.1/V5-His or S100P-overexpressing vector pcDNA3.1/S100P-V5-His into the pancreatic cancer cell line Panc1, single cell clones were then isolated. RNA was extracted and hybridized on Affymetrix microarrays. We looked for new target genes regulated by S100P.

2013-08-15 | E-GEOD-19278 | biostudies-arrayexpress

CRISPR genome-wide synthetic lethality screens of KRAS-driven mouse pancreatic ductal adenocarcinoma cells

Project description:We performed CRISPR genome-wide synthetic lethality screens to identify genetic vulnerabilities and chemogenetic interactions in KRAS-driven pancreatic cancer. We identify ERAD as a genetic target that synergizes with FTS treatment and we show that FTS treatment induces ER stress, which was further enhanced by inhibition of ERAD, leading to synergistic induction of apoptosis in pancreatic tumor cells. Altogether, our screens enable us to identify combination therapies for cancer treatment.

2020-11-25 | GSE162065 | GEO

K562 leukaemia cell line treated with thalidomide analog

Project description:We synthesized novel fluorescent thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) that localize specifically to lipid droplets. By using affinity chromatography interacting proteins were identified: Rab7, Rab10, Rab11, Sec22b, sorting nexin 2, calnexin, protein disulfide isomerase, GRP78, GRP94 among others that are involved in vesicular transport and ER stress response. Amino-trifluoro-phthalimides exerted potent anticancer activities in vitro on different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma. They are non-toxic to adult animals up-to 1 g/kg but are highly teratogenic to zebrafish embryos at micromolar concentrations resulting defects in developing muscle. The analogs resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and finally apoptosis. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as growth arrest- and DNA damage-inducible gene 153 (GADD153), ATF3, Luman/CREB3 recruitment factor (LRF) and the ER-associated degradation-related gene HERPUD1. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS and synergized with the analogs in vitro, while oleic acid had no such an effect. Different antioxidants partially, intracellular calcium chelator almost completely diminished ROS production. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis. 4 replica, 2 dye-swap

2010-02-22 | E-GEOD-14945 | biostudies-arrayexpress

S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells [HG-U133_Plus_2]

2013-08-15 | GSE19278 | GEO