Abstract
Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be determined. TR3 was overexpressed in human pancreatic tumors compared with nontumor tissue. Small interfering RNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of antiapoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo, DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, associated with inhibition of the same antiapoptotic markers observed in vitro. Our results offer preclinical validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anisoles / pharmacology
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Apoptosis / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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E1A-Associated p300 Protein / metabolism
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Gene Knockdown Techniques
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Humans
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Indoles / pharmacology*
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Inhibitor of Apoptosis Proteins
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Male
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Mice
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Mice, Nude
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Microtubule-Associated Proteins / biosynthesis
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Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors*
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / therapy*
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Phenols / pharmacology*
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Sp1 Transcription Factor / antagonists & inhibitors
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Sp1 Transcription Factor / genetics
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Survivin
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Transcriptional Activation / drug effects
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Transfection
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Xenograft Model Antitumor Assays
Substances
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1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane
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Anisoles
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BIRC5 protein, human
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Indoles
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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NR4A1 protein, human
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Phenols
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RNA, Small Interfering
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Sp1 Transcription Factor
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Survivin
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E1A-Associated p300 Protein
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EP300 protein, human