PKN1 modulates TGFß and EGF signaling in HEC-1-A endometrial cancer cell line
Sanaz Attarha,1,2 Ravi Kanth Rao Saini,3 Sonia Andersson,2 Miriam Mints,2 Serhiy Souchelnytskyi1,4,5
1Department of Oncology–Pathology, 2Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 3Department of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; 4OCD-AB, Uppsala, Sweden; 5Neurocentrum, Karolinska University Hospital, Solna, Sweden
Background: The response of cells to TGFβ and EGF is mediated by a network of various intracellular regulators. The signaling crosstalk between different regulators is of key importance for tumorigenesis. The crosstalk may explain the modulation of cellular responses to the same regulator by another signaling molecule. As PKN1 – a serine/threonine kinase implicated in tumorigenesis – was identified as potential crosstalk node for TGFβ and EGF signaling, the cellular functions that may be affected by PKN1 in a crosstalk of TGFβ and EGF were explored.
Methods: To investigate the contribution of PKN1 to TGFβ and EGF signaling, transiently PKN1-transfected HEC-1-A endometrial cancer cells were generated and subjected to treatment with TGFβ1, EGF, and their combination. Proliferation, apoptosis, invasion, wound healing, and migration assays were performed. The impact of PKN1 on the expression and phosphorylation of intracellular proteins was monitored by immunoblotting.
Results: It was demonstrated that PKN1 modulated the responses of HEC-A-1 endometrial cancer cells to TGFβ1 and EGF. PKN1 had an inhibitory effect on the stimulation of cell migration, and PKN1 kinase activity was required for the inhibitory effect of TGFβ and EGF on cell proliferation and invasiveness. It was observed that phosphorylation of Smad2, FAK, and Erk1/2 correlated with responses of the cells to TGFβ1 and EGF.
Conclusion: PKN1 modulates TGFβ- and EGF-dependent regulation of cell proliferation, migration, and invasiveness, and therefore is a component of the network signaling downstream of TGFβ and EGF.
Keywords: PKN1 kinase, TGFβ, EGF, cell migration, proliferation, invasiveness
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