Inhibition of STAT3 super(Tyr705) Phosphorylation by Smad4 Suppresses Transforming Growth Factor beta -Mediated Invasion and Metastasis in Pancreatic Cancer Cells

The role of Smad4 in transforming growth factor beta (TGF beta )-mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in expression of Smad4. Cells expressing Smad4 showed an enhanced TG...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2008-06, Vol.68 (11), p.4221-4228
Main Authors: Zhao, Shujie, Venkatasubbarao, Kolaparthi, Lazor, Jillian W, Sperry, Jane, Jin, Changqing, Cao, Lin, Freeman, James W
Format: Article
Language:English
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Summary:The role of Smad4 in transforming growth factor beta (TGF beta )-mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in expression of Smad4. Cells expressing Smad4 showed an enhanced TGF beta -mediated EMT as determined by increased expression of vimentin and decreased expression of beta -catenin and E-cadherin. TGF beta -mediated invasion was suppressed in Smad4-intact cells as determined by in vitro assays, and these cells showed a reduced metastasis in an orthotopic model of pancreatic cancer. Interestingly, TGF beta inhibited STAT3 super(Tyr705) phosphorylation in Smad4-intact cells. The decrease in STAT3 super(Tyr705) phosphorylation was linked to a TGF beta /Smad4-dependent and enhanced activation of extracellular signal-regulated kinases, which caused an increase in serine phosphorylation of STAT3 super(Ser727). Down-regulating signal transducer and activator of transcription 3 (STAT3) expression by short hairpin RNA in Smad4-deficient cells prevented TGF beta -induced invasion. Conversely, expressing a constitutively activated form of STAT3 (STAT3-C) in Smad4-intact cells enhanced invasion. This study indicates the requirement of STAT3 activity for TGF beta -induced invasion in pancreatic cancer cells and implicates Smad4-dependent signaling in regulating STAT3 activity. These findings further suggest that loss of Smad4, leading to aberrant activation of STAT3, contributes to the switch of TGF beta from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer. [Cancer Res 2008; 68(11):4221-8]
ISSN:0008-5472
1538-7445