The Orphan Nuclear Receptor NR4A1 (Nur77) Regulates Oxidative and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells

Lee, Syng‐Ook; Jin, Un Ho; Kang, Jeong Han; Kim, Sang Bae; Guthrie, Aaron S.; Sreevalsan, Sandeep; Lee, Ju Seog; Safe, Stephen

doi:10.1158/1541-7786.mcr-13-0567

Cited by 86 publications

(150 citation statements)

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“…5D) as well as induction of markers of ER stress (p-PERK, ATF4, CHOP, ATF6, IRE1, GRP78, and XBP-1s; Fig. 5E), as previously observed in pancreatic cancer cells (Lee et al 2014a). The role of ROS in mediating the effects of DIM-C-pPhCO 2 Me on activation of stress gene products was investigated in MCF-7, SKBR3, and MDA-MB-231 cells by cotreatment with the antioxidant GSH which reversed induction of the stress genes by the C-DIM/NR4A1 antagonist (Fig.…”

Section: Sinr4a1 and Dim-c-pphco 2 Me Induce Ros And Endoplasmic Retisupporting

confidence: 84%

“…Cells were visualized under an EVOS fl, Fluorescence microscope, from Advanced Microscopy Group using a multiband filter set for FITC, rhodamine, and DAPI. The C-DIM compounds were prepared and immunostaining for NR4A1 was carried out as previously described (Lee et al , 2012(Lee et al , 2014a.…”

Section: Cell Lines and Antibodiesmentioning

confidence: 99%

“…NR4A1 is overexpressed in multiple tumors and cancer cell lines. Results of receptor knockdown by RNA interference (RNAi) demonstrate that in solid tumors the receptor is pro-oncogenic and regulates cell growth and survival (Uemura & Chang 1998, Bras et al 2000, Kolluri et al 2003, Zeng et al 2006, 2014a, Wu et al 2011. Several proapoptotic agents including phorbol esters and adamantylderived retinoids induce expression and nuclear export of NR4A1 which subsequently binds mitochondrial bcl-2 to form a pro-apoptotic complex that decreases mitochondrial membrane potential (Li et al 2000, Lin et al 2004, Zhang 2007.…”

Section: Introductionmentioning

confidence: 99%

“…Studies in this laboratory have been investigating a series of 1,1-bis(3 0 -indolyl)-1-(p-substituted phenyl) methane (C-DIM) analogs and their effects on NR4A1 and NR4A1-dependent transactivation (Chintharlapalli et al 2005, Lee et al 2009, 2014a,b, Cho et al 2010. Since NR4A1 exhibits pro-oncogenic activity, we have been focused on the identification of C-DIMs that inactivate NR4A1.…”

Section: Introductionmentioning

confidence: 99%

“…Since NR4A1 exhibits pro-oncogenic activity, we have been focused on the identification of C-DIMs that inactivate NR4A1. The p-hydroxyphenyl analog (DIM-C-pPhOH) was characterized as a compound that inactivated nuclear NR4A1 in cancer cell lines but this was not accompanied by nuclear export of NR4A1 (Lee et al , 2012(Lee et al , 2014a. Subsequent studies comparing the effects of DIM-C-pPhOH and knockdown of NR4A1 (siNR4A1) by RNAi identified three major pro-oncogenic pathways and associated genes regulated by NR4A1 that were inhibited by DIM-C-pPhOH: i) NR4A1 regulates expression of genes such as survivin through interactions with specificity protein 1 (Sp1) bound to their proximal GC-rich promoters ; ii) NR4A1 inactivates p53 to enhance mTOR signaling in lung and colon cancer cells expressing WT p53 (Lee et al 2012(Lee et al , 2014b; and iii) NR4A1 regulates expression of thioredoxin domain-containing 5 (TXNDC5) and isocitrate dehydrogenase 1 (IDH1) to maintain low levels of oxidative stress (Lee et al 2014a;Fig.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick¹,

Lee²,

Doddapaneni³

et al. 2015

Endocrine-Related Cancer

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The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3 0 -indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis.The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.

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Section: Sinr4a1 and Dim-c-pphco 2 Me Induce Ros And Endoplasmic Retisupporting

confidence: 84%

Section: Cell Lines and Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick¹,

Lee²,

Doddapaneni³

et al. 2015

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

Clinical candidate and genistein analogue AXP107‐11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein‐coupled estrogen receptor signaling

et al. 2019

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Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107‐11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient‐derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107‐11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA‐Seq from responsive and unresponsive tumors proposed a 41‐gene treatment‐predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G‐protein‐coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1‐selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics.

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Identification of thioredoxin domain containing family members' expression pattern and prognostic value in diffuse gliomas via in silico analysis

Kocatürk

2022

Cancer Medicine

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Background Gliomas are the most prevalent primary tumors of the central nervous system. Their aggressive nature and the obstacles arising during therapy highlights the importance of finding new prognostic markers and therapy targets for gliomas. TXNDC genes are members of the thioredoxin superfamily and were shown to play a role in redox homeostasis, protein folding, electron transfer and also acting as cellular adapters. The well known contribution of these processes in cancer progression prompted us to investigate if TXNDC family members may also play a role in carcinogenesis, in particular diffuse gliomas. Methods The present study used in silico analysis tools GEPIA, UCSC Xena, Gliovis, cBioPortal, and Ivy GAP to evaluate the expression pattern, prognostic value and clinical significance of TXNDC family members in diffuse gliomas. Results Our analysis showed that TXNDC family members' expression pattern differ between tumors and healthy tissues and among tumors with different grades. The detailed analysis of TXNDC5 in glioma pathogenesis revealed that TXNDC5 expression is associated with more aggressive clinical and molecular features and poor therapy success both in LGG and GBM samples. Kaplan–Meier survival curves represented a worse prognosis for patients with leveated TXNDC5 levels in LGG and all grade glioma patients. The levels of TXNDC5 was shown to be possibly regulated by hypoxia‐ER stress axis and a potential mechanism for TXNDC5‐driven glioma progression was found to be extracellular matrix (ECM) production which is known to promote tumor aggressiveness. Conclusions Our results uncovered the previously unknown role of TXNDC family members in glioma pathogenesis and showed that TXNDC5 levels could serve as a predictor of clinical outcome and therapy success and may very well be used for targeted therapy.

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The Orphan Nuclear Receptor NR4A1 (Nur77) Regulates Oxidative and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells

Cited by 86 publications

References 44 publications

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Clinical candidate and genistein analogue AXP107‐11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein‐coupled estrogen receptor signaling

Identification of thioredoxin domain containing family members' expression pattern and prognostic value in diffuse gliomas via in silico analysis

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