Involvement of ERK1/2/NF-κB signal transduction pathway in TF/FVIIa/PAR2-induced proliferation and migration of colon cancer cell SW620.

Abstract

Our previous study has demonstrated that TF/FVIIa and protease-activated receptor 2 (PAR2) are closely related to the proliferation and migration of colon cancer cell line SW620. However, the detailed signaling cascades and underlying molecular mechanisms remain unclear. This study has investigated whether extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor kappaB (NF-κB) signaling pathways are involved in the events. The results revealed that PAR2-activating peptide (PAR2-AP) or FVIIa elicited time-dependent upregulation of ERK1/2 phosphorylation in SW620 cells, and the effect of FVIIa was significantly attenuated by anti-TF antibody. PAR2-AP or FVIIa also increased NF-κB (p65/RelA) levels among cell nuclear proteins and simultaneously decreased IκB-α levels in the cytoplasmic proteins. Such effects of FVIIa can be inhibited with anti-PAR2 or anti-TF antibodies. While ERK1/2 inhibitor (U0126) intervened with the regulatory effects of PAR2-AP and FVIIa on IκB-α/NF-κB (p65/Rel) expression in the cells, NF-κB inhibitor (PDTC) partially blocked the enhancing effects of PAR2-AP and FVIIa on the proliferating and migratory ability of SW620 cells. Furthermore, the regulatory effects of PAR2-AP and FVIIa on expressions of certain proteins (IL-8, caspase-7, and TF) were also significantly abolished by PDTC. Collectively, the data in this study suggest that the interaction between FVIIa and TF induces PAR2 activation, thereby triggers the ERK1/2 and IκB-α/NF-κB signal transduction pathway to regulate the gene expression of IL-8, TF, and caspase-7, and ultimately promotes SW620 cell proliferation and migration.

• Authors: Donglin Guo, Hong Zhou, Ying Wu, Fang Zhou, Guoying Xu, Haiping Wen, Xianmei Zhang
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 32 Issue 5 Pg. 921-30 (Oct 2011) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 21625939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• NF-kappa B
• Receptor, PAR-2
• Thromboplastin
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Factor VIIa
• Caspase 7

Topics

• Blotting, Western
• Caspase 7 (biosynthesis)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cell Proliferation
• Colonic Neoplasms (metabolism, pathology)
• Enzyme Activation (physiology)
• Factor VIIa (metabolism)
• Flow Cytometry
• Gene Expression Regulation (physiology)
• Humans
• Interleukin-8 (biosynthesis)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Receptor, PAR-2 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Thromboplastin (metabolism)