Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth.
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.
Lee
Syng-Ook
SO
Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX, USA.
Abdelrahim
Maen
M
Yoon
Kyungsil
K
Chintharlapalli
Sudhakar
S
Papineni
Sabitha
S
Kim
Kyounghyun
K
Wang
Huamin
H
Safe
Stephen
S
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010636:Phenols / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics; D000077022:Survivin; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; D000840:Anisoles; C107489:BIRC5 protein, human; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D000077022:Survivin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human