Domain 5 of kininogen inhibits proliferation of human colon cancer cell line (HCT-116) by interfering with G1/S in the cell cycle.
Background: Domain 5 (D5) of kininogen inhibits endothelial cell adhesion, migration, proliferation and angiogenesis by inducing apoptosis and disrupting a signaling pathway initiated by binding to the urokinase receptor (uPAR). Objectives: Because tumor cells frequently overexpress uPAR, we hypothesized that D5 can directly inhibit proliferation of colon carcinoma cells. Methods and results: A recombinant fusion protein of D5 and glutathione S-transferase (GST-D5) but not GST at 280 nm inhibited proliferation of human colon carcinoma cells (HCT-116) in vitro by 75-86%. We found that treatment with GST-D5 did not affect the survival pathway, phosphatidylinositol 3-kinase or the apoptotic pathway. In contrast, the G1/S phase transition of the cell cycle was downregulated as evidenced by an increase of cells in G0/G1 and a decrease in cells in S by flow cytometry. We found a decrease in serine phosphorylation of the retinoblastoma protein Rb (p107) after incubation with GST-D5. Less E2F-1 transcription factor and p107 were released and fewer cells overcame the G1/S growth restriction point. Expression levels of cyclins D1, A and E were reduced as measured by densiometric analysis of western blots. Cyclin-dependent protein kinase activities were downregulated and p27, the cyclin-dependent kinase inhibitor, was activated by GST-D5. Conclusions: These findings indicate that D5 of high molecular weight kininogen interferes with the G1 to S phase transition, reducing the proliferation of human colon carcinoma cells.[1]References
- Domain 5 of kininogen inhibits proliferation of human colon cancer cell line (HCT-116) by interfering with G1/S in the cell cycle. Bior, A.D., Pixley, R.A., Colman, R.W. J. Thromb. Haemost. (2007) [Pubmed]
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