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. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Bartscht, Tobias; Rosien, Benjamin; Rades, Dirk; Kaufmann, Roland; Biersack, Harald; Lehnert, Hendrik; Gieseler, Frank; Ungefroren, Hendrik
• Is Part Of: Molecular cancer. Volume 14:Issue 1(2015)
• Page Start: 1
• Page End: 12
• Publication Date: 2015-12
• Subjects: Dasatinib -- TGF-β -- Smad -- PDAC -- Cell migration -- Invasion -- Activin receptor-like kinase 5; Cancer -- Molecular aspects -- Periodicals; 616.994
• DOI: 10.1186/s12943-015-0468-0
• Languages: English
• ISSNs: 1476-4598

Abstract

Abstract Background We 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. Methods The 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. Results In 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. Conclusions Our 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.