TGF-β downregulates PTEN via activation of NF-κB in pancreatic cancer cells
Autor: | John M. Carethers, Mei Huang, Makiko Ban, Heekyung Chung, Helen L. Wu, Flang Nguyen, Jimmy Y. C. Chow, Hui Dong |
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Rok vydání: | 2010 |
Předmět: |
Physiology
Hormones and Signaling Smad2 Protein SMAD Adenocarcinoma Biology chemistry.chemical_compound NF-KappaB Inhibitor alpha Cell Movement Genes Reporter Transforming Growth Factor beta Cell Line Tumor Physiology (medical) TGF beta signaling pathway Humans PTEN Smad3 Protein Phosphorylation Smad4 Protein Hepatology PTEN Phosphohydrolase Transcription Factor RelA Gastroenterology NF-κB Transforming growth factor beta chemistry Cancer research biology.protein I-kappa B Proteins Signal transduction Cell Division Carcinoma Pancreatic Ductal Signal Transduction Transforming growth factor |
Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 298:G275-G282 |
ISSN: | 1522-1547 0193-1857 |
DOI: | 10.1152/ajpgi.00344.2009 |
Popis: | 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. |
Databáze: | OpenAIRE |
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