alpha-Thrombin inhibits DNA synthesis in rat hepatocytes but not in hepatoma cells by receptor activation and proteolysis.
Prothrombin is a plasma protein, which after tissue injury is converted to alpha-thrombin and is mainly involved in blood clot formation. It has also been shown to have a mitogenic effect on primary endothelial cells, vascular smooth muscle cells, fibroblasts and some tumor cells, but is an inhibitor of rat hepatocyte DNA synthesis on fibronectin matrix in cell culture. We now report that prothrombin is converted to alpha-thrombin by primary cultures of normal adult rat hepatocytes and alpha-thrombin is also a potent inhibitor of hepatocytes DNA synthesis. In contrast, rat hepatoma cells cultured under similar conditions were resistant to alpha-thrombin mediated DNA synthesis inhibition. The inhibitory effect of alpha-thrombin on DNA synthesis was antagonized by hirudin and antithrombin, two specific alpha-thrombin inhibitors or by the presence of collagen-I matrix. A thrombin receptor activating peptide (TRAP6) also inhibited EGF-mediated rat hepatocyte DNA synthesis, suggesting a role of the thrombin receptors in this process. Matrix fibronectin was degraded by alpha-thrombin. However, no appreciable cell detachment was observed. These results suggest a role of alpha-thrombin as a potent growth inhibitor of normal hepatocytes, possibly through control of fibronectin or other matrix protein(s).
Kar
Siddhartha
S
Liver Cancer Center, T. E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, E1550, BST, Pittsburgh, PA 15260, USA.
Wang
Meifang
M
Carr
Brian I
BI
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011516:Prothrombin / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018179:Receptors, Thrombin / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D005353:Fibronectins; D019384:Nucleic Acid Synthesis Inhibitors; D018179:Receptors, Thrombin; D011516:Prothrombin; D004247:DNA; D013917:Thrombin