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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2010-1-26
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pubmed:abstractText |
TGF-beta utilizes receptor-activated SMAD signaling to mediate growth suppression; however, non-SMAD signaling that modulates the TGF-beta response in epithelial cells become apparent when the SMAD signaling is abrogated, a common occurrence in pancreatic cancers. Here, we examined whether TGF-beta utilized NF-kappaB to downregulate PTEN, a gene that is rarely mutated in pancreatic cancers. SMAD4-null BxPc3 and CAPAN-1 pancreatic cancer cells were treated with TGF-beta (10 ng/ml) and lysed, and cellular proteins were analyzed by Western blots using p-IkappaB, p65, and PTEN antibodies. PTEN promoter and NF-kappaB activities were assessed by PTEN-luc and p-NF-luc constructs, respectively. Dominant negative p-IkappaB-alpha-M (NF-kappaB superrepressor) was used to block activation of NF-kappaB. Cell motility was assessed by Boyden chamber migration assay. TGF-beta induced IkappaB-alpha phosphorylation followed by NF-kappaB p65 subunit nuclear translocation and increased NF-kappaB activity. IkappaB-alpha-M blocked TGF-beta-induced NF-kappaB activity, reversed downregulated PTEN promoter activity and PTEN expression, and prevented augmentation of cell motility induced by TGF-beta. SMAD4 restoration, but not knockdown of SMAD2 and/or 3, reversed TGF-beta-induced NF-kappaB activity. Thus TGF-beta suppresses PTEN in pancreatic cancer cells through NF-kappaB activation and enhances cell motility and invasiveness in a SMAD4-independent manner that can be counteracted when TGF-beta-SMAD signaling is restored. The TGF-beta/NF-kappaB/PTEN cascade may be a critical pathway for pancreatic cancer cells to proliferate and metastasize.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappaB inhibitor alpha,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN Phosphohydrolase,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Smad2 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1522-1547
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
298
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
G275-82
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pubmed:dateRevised |
2011-9-22
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pubmed:meshHeading |
pubmed-meshheading:19940030-Adenocarcinoma,
pubmed-meshheading:19940030-Carcinoma, Pancreatic Ductal,
pubmed-meshheading:19940030-Cell Division,
pubmed-meshheading:19940030-Cell Line, Tumor,
pubmed-meshheading:19940030-Cell Movement,
pubmed-meshheading:19940030-Genes, Reporter,
pubmed-meshheading:19940030-Humans,
pubmed-meshheading:19940030-I-kappa B Proteins,
pubmed-meshheading:19940030-PTEN Phosphohydrolase,
pubmed-meshheading:19940030-Phosphorylation,
pubmed-meshheading:19940030-Signal Transduction,
pubmed-meshheading:19940030-Smad2 Protein,
pubmed-meshheading:19940030-Smad3 Protein,
pubmed-meshheading:19940030-Smad4 Protein,
pubmed-meshheading:19940030-Transcription Factor RelA,
pubmed-meshheading:19940030-Transforming Growth Factor beta
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pubmed:year |
2010
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pubmed:articleTitle |
TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells.
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pubmed:affiliation |
Division of Gastroenterology, Department of Medicine, University of California-San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0063, USA. ycchow@ucsd.edu
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, N.I.H., Extramural
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