Dasatinib blocks transcriptional and promigratory responses to transforming growth factor-beta in pancreatic adenocarcinoma cells through inhibition of Smad signalling: implications for in vivo mode of action

Molecular Cancer

Research

Roland Kaufmann¹  Dirk Rades²  Hendrik Ungefroren³  Tobias Bartscht³  Hendrik Lehnert³  Frank Gieseler³  Harald Biersack³  Benjamin Rosien³ 

[1] Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747, Jena, Germany;Department of Radiation Oncology, UKSH, Campus Lübeck, D-23538, Lübeck, Germany;First Department of Medicine, UKSH, Campus Lübeck, 23538, Lübeck, Germany;

关键词: Dasatinib;    TGF-β;    Smad;    PDAC;    Cell migration;    Invasion;    Activin receptor-like kinase 5;   

DOI  :  10.1186/s12943-015-0468-0

 received in 2015-06-17, accepted in 2015-11-08,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundWe have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-β1-mediated cellular responses by blocking the kinase function of the TGF-β type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect.MethodsThe effect of dasatinib on TGF-β1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively.ResultsIn both PDAC cell lines, dasatinib effectively blocked TGF-β1-induced Smad phosphorylation, activity of 3TPlux and pCAGA(12)-luc reporter genes, cell migration, and expression of individual TGF-β1 target genes associated with epithelial-mesenchymal transition and invasion. Moreover, dasatinib strongly interfered with the TGF-β1-induced generation of tumour stem cells as demonstrated by gene expression analysis and single cell colony formation. Dasatinib also inhibited the high constitutive migratory activity conferred on Panc-1 cells by ectopic expression of kinase-active ALK5.ConclusionsOur data suggest that the clinical efficiency of dasatinib may in part be due to cross-inhibition of tumour-promoting TGF-β signalling. Dasatinib may be useful as a dual TGF-β/SRC inhibitor in experimental and clinical therapeutics to prevent metastatic spread in late-stage PDAC and other tumours.

【 授权许可】

CC BY   
© Bartscht et al. 2015