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

被引：28

作者：

Bartscht, Tobias ^{[1
]}

Rosien, Benjamin ^{[1
]}

Rades, Dirk ^{[2
]}

Kaufmann, Roland ^{[3
]}

Biersack, Harald ^{[1
]}

Lehnert, Hendrik ^{[1
]}

Gieseler, Frank ^{[1
]}

Ungefroren, Hendrik ^{[1
]}

机构：

[1] UKSH, Dept Med 1, D-23538 Lubeck, Germany

[2] UKSH, Dept Radiat Oncol, D-23538 Lubeck, Germany

[3] Jena Univ Hosp, Dept Gen Visceral & Vasc Surg, D-07747 Jena, Germany

来源：

MOLECULAR CANCER | 2015年 / 14卷

关键词：

Dasatinib; TGF-beta; Smad; PDAC; Cell migration; Invasion; Activin receptor-like kinase 5; SRC KINASE; MESENCHYMAL TRANSITION; DUCTAL ADENOCARCINOMA; TYROSINE KINASES; FACTOR RECEPTOR; SOLID TUMORS; CANCER; EXPRESSION; RESISTANCE; PROLIFERATION;

D O I：

10.1186/s12943-015-0468-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Background: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-beta 1-mediated cellular responses by blocking the kinase function of the TGF-beta 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-beta 1-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-beta 1-induced Smad phosphorylation, activity of 3TPlux and pCAGA(12)-luc reporter genes, cell migration, and expression of individual TGF-beta 1 target genes associated with epithelial-mesenchymal transition and invasion. Moreover, dasatinib strongly interfered with the TGF-beta 1-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-beta signalling. Dasatinib may be useful as a dual TGF-beta/SRC inhibitor in experimental and clinical therapeutics to prevent metastatic spread in late-stage PDAC and other tumours.

引用

页数：12

共 42 条

[1]

[Anonymous], 2011, J VIS EXP, DOI DOI 10.3791/2573

[2]

Dynamic and label-free cell-based assays using the real-time cell electronic sensing system [J].