Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation

Keren S. Borensztajn*, Maarten F. Bijlsma, Angelique P. Groot, Lois W. Brüggemann, Henri H. Versteeg, Pieter H. Reitsma, Maikel P. Peppelenbosch, C. Arnold Spek

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

Coagulation Factor (F)Xa is a serine protease that plays a crucial role during blood coagulation by converting prothrombin into active thrombin. Recently, however, it emerged that besides this role in coagulation, FXa induces intracellular signaling leading to different cellular effects. Here, we show that coagulation factor (F)Xa drives tumor cells of epithelial origin, but not endothelial cells or monocytes, into apoptosis, whereas it even enhances fibroblast survival. FXa signals through the protease activated receptor (PAR)-1 to activate extracellular-signal regulated kinase (ERK) 1/2 and p38. This activation is associated with phosphorylation of the transcription factor CREB, and in tumor cells with up-regulation of the BH3-only pro-apoptotic protein Bim, leading to caspase-3 cleavage, the main hallmark of apoptosis. Transfection of tumor cells with dominant negative forms of CREB or siRNA for either PAR-1, Bim, ERK1 and/or p38 inhibited the pro-apoptotic effect of FXa. In fibroblasts, FXa-induced PAR-1 activation leads to down-regulation of Bim and pre-treatment with PAR-1 or Bim siRNA abolishes proliferation. We thus provide evidence that beyond its role in blood coagulation, FXa plays a key role in cellular processes in which Bim is the central player in determining cell survival.

Original languageEnglish
Pages (from-to)2622-2633
Number of pages12
JournalExperimental Cell Research
Volume313
Issue number12
DOIs
Publication statusPublished - 15 Jul 2007
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Inge Pronk for technical assistance. KB is supported by the Fondation pour la Recherche Medicale, MB is supported by STW Technology Foundation and LB is supported by the Netherlands Heart Foundation.

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