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Meizothrombin, an intermediate of prothrombin cleavage potently activates renal carcinoma cells by interaction with
R Kaufmann1, U Junker, M Schilli-Westermann
1Research Laboratory, Department of General and Visceral Surgery, Institute of Immunology, Medical Faculty at the Friedrich Schiller University Jena, Research Center Lobeda, Germany. roland.kaufmann@med.uni-jena.de
Abstract:
Recently, meizothrombin (MT), an intermediate enzyme in the prothrombin cleavage cascade has been shown to activate cells of a brain tumor cell line by interaction with PAR-1-type thrombin receptors with a potency comparable to that of thrombin. In this study, we investigated the effect of recombinant human MT (rMT) on calcium mobilization in primary cultures established from surgically resected human renal cell carcinomas. Meizothrombin induced very rapidly transient calcium mobilization in RCC cells comparable to that observed with thrombin. RCC cells stimulated with thrombin after rMT challenge were unable to elicit a new calcium response and vice versa. Therefore, rMT and thrombin seem to activate calcium signaling in primary RCC cultures by similar mechanisms including PAR-1- and PAR-3-type thrombin receptors as shown by using PAR-type specific antibodies. Our results demonstrate rMT as a potent activator of human RCC cells suggesting a function of not only thrombin but also of this catalytically active thrombin precursor enzyme in human renal cell carcinoma.
Insights
Meizothrombin (MT) activates renal cell carcinoma (RCC) cells, similar to thrombin, by engaging PAR-1 and PAR-3 receptors. This suggests MT, a thrombin precursor, plays a role in RCC progression.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Meizothrombin (MT), a prothrombin intermediate, activates brain tumor cells via PAR-1 receptors.
- Its role in renal cell carcinoma (RCC) is not well understood.
Purpose of the Study:
- To investigate the effect of recombinant human MT (rMT) on calcium mobilization in primary human RCC cultures.
- To determine the specific thrombin receptors involved in rMT-mediated RCC cell activation.
Main Methods:
- Primary human RCC cell cultures were established.
- Calcium mobilization was measured in response to rMT and thrombin stimulation.
- PAR-type specific antibodies were used to identify involved receptors.
Main Results:
- rMT rapidly induced transient calcium mobilization in RCC cells, similar to thrombin.
- Stimulation with thrombin after rMT (and vice versa) did not elicit a new calcium response, indicating shared pathways.
- PAR-1 and PAR-3 receptors were implicated in rMT-induced calcium signaling.
Conclusions:
- rMT is a potent activator of human RCC cells.
- Both thrombin and MT may play significant roles in human renal cell carcinoma.
- rMT's activation mechanism in RCC involves PAR-1 and PAR-3 receptors.