TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells
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Natalia Smoktunowicz1, Manuela Platé1, Alejandro Ortiz Stern1, Vanessa D’Antongiovanni1, Eifion Robinson2, Vijay Chudasama2, Stephen Caddick2, Chris J. Scotton1, Gabor Jarai3, Rachel C. Chambers1
1Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK
2Department of Chemistry, University College London, London, UK
3Novartis Institutes of Biomedical Research, Horsham, UK
Rachel C. Chambers, email: [email protected]
Keywords: PAR-1, TGFβ, thrombin, cancer
Received: February 12, 2016 Accepted: August 06, 2016 Published: August 22, 2016
The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.
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