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

Borensztajn, Keren; Bijlsma, Maarten F.; Groot, A. P. De; Brüggemann, Lois W.; Versteeg, Henri H.; Reitsma, Pieter H.; Peppelenbosch, Maikel P.; Spek, C. Arnold

doi:10.1016/j.yexcr.2007.04.014

Cited by 29 publications

(35 citation statements)

References 56 publications

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“…In contrast to these results, Borensztajn et al () demonstrated that FXa‐induced PAR‐1 activation induces tumor cells apoptosis through activation of ERK1/2 and p38 pathways and over‐expression of the proapoptotic protein Bim. Interestingly, in the same study they found that FXa upon cleavage of PAR‐1 down‐regulates Bim expression and induces cell proliferation in fibroblasts, suggesting that the effect of FXa on cell apoptosis is cell‐dependent and Bim protein is the key player in FXa‐induced cell survival (Borensztajn et al, ). Consistent with the anticancer effects of FXa, they showed that FXa‐induced PAR‐1 activation inhibits migration of breast, lung, and colon cancer cells through regulation of the Rho/ROCK and Src/FAK/paxillin signaling pathways (Borensztajn et al, ).…”

Section: Signaling Properties Of Fxamentioning

confidence: 87%

Factor Xa Signaling Contributes to the Pathogenesis of Inflammatory Diseases

Ebrahimi

Rezaei

Seiri

et al. 2016

Journal Cellular Physiology

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The coagulation protease Factor Xa (FXa) triggers a variety of signaling pathways through activation of protease-activated receptors (PARs) and non-PAR receptors. FXa-mediated signaling is strongly implicated in the pathogenesis of several inflammatory diseases including fibrosis, cardiovascular diseases, and cancer. Thus, targeting of FXa can have great clinical significance in terms of the treatment of these disorders. This review summarizes the current knowledge about the mechanism of FXa signaling in cellular and animal systems under (patho) physiological conditions for a better understanding and hence a better management of FXa-induced disorders. J. Cell. Physiol. 232: 1966-1970, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Signaling Properties Of Fxamentioning

confidence: 87%

Factor Xa Signaling Contributes to the Pathogenesis of Inflammatory Diseases

Ebrahimi

Rezaei

Seiri

et al. 2016

Journal Cellular Physiology

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“…The resistant clone PC-9/ BB4 was generated by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) according to the method of Keren S et al [21]. The cells were maintained in a humidified incubator with 5% CO 2 at 37°C in DMEM medium supplemented with 10% fetal bovine serum and pen-strep solution (both from Gemini Bio-Products, West Sacramento, CA; final concentrations of 100 U/ml penicillin G and 100 lg/ml streptomycin, respectively).…”

Section: Cell Culturementioning

confidence: 99%

“…After transfection of siRNA, BIM expression levels and apoptotic cell numbers induced by gefitinib were attenuated in both cell lines (Fig. 4), and the attenuation was Cells were examined for mutations in EGFR by dideoxynucleotide sequencing of PCR products spanning individual exons (18)(19)(20)(21). The IC 50 values were determined using MTT assays as described in methods more obvious in PC-9 cell line.…”

Section: Knockdown Of Bim Attenuated Tki-induced Apoptosismentioning

confidence: 99%

BIM induction of apoptosis triggered by EGFR-sensitive and resistance cell lines of non-small-cell lung cancer

Zhou

Zhang

et al. 2010

Med Oncol

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We sought to improve the understanding of oncogene-dependent and independent non-small-cell lung cancer (NSCLC), which could provide insight into mechanism of sensitivity and/or resistance to tyrosine kinase inhibitors or chemotherapeutics. NSCLC cell lines with different EGFR genotypes were used in this study; MTT assay and flow cytometry were applied to study the sensitivities of these cell lines to gefitinib and cisplatin. Western blot was performed to determine the expression levels of BIM and other Bcl-2 family proteins pre- and pro-treatment. Gefitinib provoked apoptosis of caspase activation via the intrinsic pathways and significantly up-regulated expression of BIM protein in drug-sensitive PC-9 cell line, but not resistant PC-9/BB4 cell line. The knockdown of BIM expression by RNA interference virtually eliminated gefitinib-induced cell killing in PC-9 cells in vitro. Cisplatin could induce apoptosis of the cell lines, including H1299, A549, PC-9, and PC-9/BB4 cells, but which was not associated with overexpression of BIM. BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cell line. Down-regulation of BIM and resistance to gefitinib were both seen in the acquired resistant PC-9/BB4 cell line. The induction of BIM may have a role in the treatment of TKI-resistant tumors.

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“…Importantly, PAR-1 agonist peptides also induced apoptosis in the cancer cell lines tested though at much higher concentrations (25-100 M ) than thrombin. In addition, PAR-1 activation by coagulation FXa induces apoptosis in several cancer cell lines independent of its concentration [70] . Thus, PAR-1 activation might mediate tumor growth but might also induce apoptosis indicating a pleiotropic role of this receptor in tumor biology.…”

Section: Protease-activated Receptors Tumor Growth and Apoptosismentioning

confidence: 99%

“…However, different studies addressing this question in different cell types (fibroblasts, cancer cells and neurons) all point to a crucial role of the pro-apoptotic BH3-only protein Bim. If Bim levels are induced after PAR-1 activation, cells are driven into apoptosis [70,85] . In contrast, if Bim levels are down-regulated, PAR-1 activation leads to enhanced cell survival [60,76] .…”

Section: Protease-activated Receptors Tumor Growth and Apoptosismentioning

confidence: 99%

Protease-Activated Receptors, Apoptosis and Tumor Growth

Borensztajn

Spek

2007

Pathophysiol Haemos Thromb

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Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.

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

Cited by 29 publications

References 56 publications

Factor Xa Signaling Contributes to the Pathogenesis of Inflammatory Diseases

Factor Xa Signaling Contributes to the Pathogenesis of Inflammatory Diseases

BIM induction of apoptosis triggered by EGFR-sensitive and resistance cell lines of non-small-cell lung cancer

Protease-Activated Receptors, Apoptosis and Tumor Growth

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