TGF-β Signal Transduction in Pancreatic Carcinoma Cells is Sensitive to Inhibition by the Src Tyrosine Kinase Inhibitor AZM475271

Author(s): Tobias Bartscht, Benjamin Rosien, Dirk Rades, Roland Kaufmann, Harald Biersack, Hendrik Lehnert, Hendrik Ungefroren*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , Issue 7 , 2017

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Abstract:

Background: Earlier results from our group have shown that in pancreatic ductal adenocarcinoma (PDAC)-derived cells transforming growth factor (TGF)-β1-dependent epithelial-mesenchymal transition (EMT) and cell motility was inhibited by the Src inhibitors PP2 and PP1 both of which targeted the TGF-β receptors for inhibition.

Objective: In this study we evaluated the impact of another Src inhibitor, AZM475271, on various TGF-β responses in PDAC cells.

Method: The effect of AZM475271 on TGF-β1-induced random cell migration (chemokinesis), the expression of EMT and migration/invasion-associated genes, TGF-β-induced luciferase activity, and C-terminal phosphorylation of Smad2 and Smad3 was measured in the PDAC-derived Panc-1 and Colo357 cell lines using real-time cell migration assays, quantitative real-time PCR, luciferase reporter gene assays and phosphoimmunoblotting, respectively.

Results: AZM475271 effectively blocked TGF-β1-induced chemokinesis of Panc-1 cells in a dose-dependent fashion and inhibited the high chemokinetic activity of Panc-1 cells with ectopic expression of a constitutively active ALK5T204D mutant. AZM475271 but not another Src inhibitor, SU6656, partially relieved the suppressive effect of TGF-β1 on E-cadherin and inhibited TGF-β1-induced upregulation of the MMP2, MMP9, N-cadherin and vimentin genes, activity of a TGF-β1-dependent reporter gene, and activation of Smad2 and Smad3.

Conclusion: Our data suggest that AZM475271 cross-inhibits tumor-promoting TGF-β signaling and may thus function as an inhibitor of both TGF-β and Src in both experimental and clinical therapies against metastatic dissemination in late-stage PDAC.

Keywords: AZM475271, ALK5, chemokinesis, PDAC, Smad, TGF-β.

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Article Details

VOLUME: 17
ISSUE: 7
Year: 2017
Page: [966 - 972]
Pages: 7
DOI: 10.2174/1871520616666160926110513
Price: $58

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