Journal
TUMOR BIOLOGY
Volume 34, Issue 5, Pages 2573-2581Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-013-0803-2
Keywords
Tissue factor; Factor VIIa; Protease-activated receptor 2; SW620 cells; c-Jun/AP-1
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Funding
- Sci-tech Innovation Team of Jiangsu Province [LJ201116]
- Key Laboratory of Cardiovascular disease of Zhenjiang [SS2012002]
- Natural Science Foundation of Jiangsu Province [BK2010336]
- Student's Scientific Research of Jiangsu University [Y11A183]
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Our previous study has demonstrated that tissue factor-factor VIIa (TF/FVIIa) complex promotes the proliferation and migration of colon cancer cell line SW620 through the activation of protease-activated receptor 2 (PAR2). In the current study, the underlying molecular mechanisms of TF/FVIIa/PAR2 signaling in SW620 cells were further explored, with the focus on the role of activator protein-1 (AP-1) subunit c-Jun. The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C alpha (PKC alpha) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun. In contrast, Ca2+ chelators EGTA and thapsigargin, and p38MAPK inhibitor SB203580 had no effect. Suppression of c-Jun/AP-1 activation using a natural inhibitor curcumin decreased the expression of caspase-3, MMP-9, and TF, as well as the proliferation and migration of SW620 cells induced by PAR2-AP or FVIIa. Collectively, our findings suggest that c-Jun/AP-1 activation is required for TF/FVIIa/PAR2-induced SW620 cell proliferation and migration. PKC alpha and ERK1/2 are located upstream of c-Jun/AP-1 in this signaling pathway. Pharmacological inhibition of this pathway might be a novel strategy for colon cancer therapy.
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