title: The orphan nuclear receptor NR4A1 (Nur77) 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 and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.
  
  
  CONCLUSIONS
  The NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer.
authors: Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.|Department of Food Science and Technology, Keimyung University, Daegu 704-701, Republic of Korea.
authors: Syng-Ook
authors: SO
authors: Lee
authors: Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors: Un-Ho
authors: UH
authors: Jin
authors: Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Jeong Han
authors: JH
authors: Kang
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors: Sang Bae
authors: SB
authors: Kim
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors: Aaron S
authors: AS
authors: Guthrie
authors: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
authors: Sandeep
authors: S
authors: Sreevalsan
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors: Ju-Seog
authors: JS
authors: Lee
authors: Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.|Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
authors: Stephen
authors: S
authors: Safe
mesh_terms: D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010636:Phenols / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007211:Indoles; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D017382:Reactive Oxygen Species; D019704:Protein Disulfide-Isomerases; C480743:TXNDC5 protein, human