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Simvastatin induces apoptosis in human breast cancer cells in a NFκB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer Pharmacology and Informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2008 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 122, no 2, 191-202 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Statins have benefits independent of the plasma cholesterol properties among cancer patients and tissue factor (TF)/FVIIa induce PI3-kinase/AKT dependent anti-apoptosis during serum starvation. We analyzed how simvastatin induces apoptosis in human breast cancer cells and the influence of FVIIa and/or FXa on the proposed apoptosis. Materials and methods: MDA-MB-231 cells were serum starved or treated with 5 μM simvastatin and incubated with 10 and 100 nM FVIIa or 5/130 nM FVIIa/FX. RhoA was analyzed by confocal microscopy and caspase-3, nuclear fragmentation, and NFκB translocation were measured using the ArrayScan microscope. mRNA for BCL-2, AKT1 and TF were analyzed with RT-PCR or TaqMan. Protein levels and phosphorylation of PKB/AKT were determined by western blotting. Results and conclusions: Simvastatin-induced apoptosis was recorded at 48 h in the MDA-MB-231 cells. Addition of FVIIa to the cells induced PKB/AKT phosphorylation at 24 h and rescued serum-deprived cells from apoptosis. However, in the presence of simvastatin we were unable to report any phosphorylation of PKB/AKT or anti-apoptotic effect mediated by the TF/FVIIa or TF/FVIIa/FXa complexes. This was due to a RhoA-dependent retention of NFκB to the cytosol at 12 h which led to a transcriptional down-regulation of the anti-apoptotic protein BCL-2 as well as reduced AKT1 mRNA production at 24 h and thus diminished levels of PKB/AKT protein. A transcriptional down-regulation of TF at 12 h possibly also contributed to the absent anti-apoptotic signaling. These results thereby support a role for simvastatin in cancer treatment and emphasize the importance of PKB/AKT in TF-signaling.

Place, publisher, year, edition, pages
2008. Vol. 122, no 2, 191-202 p.
Keyword [en]
Statins, Apoptosis, NFκB, Tissue factor, FVIIa, Cell signaling
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97673DOI: 10.1016/j.thromres.2007.09.017ISI: 000257282500008PubMedID: 18031796OAI: oai:DiVA.org:uu-97673DiVA: diva2:172704
Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2012-07-12Bibliographically approved
In thesis
1. Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
Open this publication in new window or tab >>Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. TF is over-expressed on many malignant cells and apart from increasing the risk of thrombosis, the presence of TF/FVIIa also promotes the progression of cancer and metastasis by intracellular signaling. TF expressing microparticles (MP) are, moreover, often found in the circulation of cancer patients.

Aim: The aim of this thesis was to study different aspects of TF activity, e.g. the importance of procoagulant MP and TF-induced intracellular signaling pathways, with focus on cell migration (chemotaxis) and apoptosis.

Results: The TF signaling complexes were shown to prevent apoptosis induced by serum starvation and TRAIL in cancer cells by reduced activation of caspase-8 in a PI3k/AKT-dependent manner. FVIIa also decreased transcription of pro-apoptotic genes in cancer cells treated with TRAIL. Simvastatin triggered apoptosis by transcriptional reduction of BCL-2 due to cytosolic retention of NFκB. Simvastatin also inactivated the PI3k/AKT pathway and reduced the production of the MP-like prostasomes which, respectively, impaired the anti-apoptotic signaling by TF and reduced the procoagulant activity in the vicinity of prostate cancer cells. Intracellular events conducted by the TF/FVIIa complex selectively enhanced PDGF-BB induced chemotaxis which was partly explained by the TF/FVIIa-induced transactivation of the PDGFβ-receptor. This was dependent on Src-family members and engagement of PAR2.

Conclusions: The results presented in this thesis extend the current knowledge of TF-mediated signaling. We report the TF complexes to govern the extrinsic pathway of apoptosis, present data on FVIIa-dependent regulation of apoptosis-related genes, and exclude known surface proteins as transmitters of the anti-apoptotic signals. We moreover describe TF/FVIIa to transactivate the PDGFβ-receptor and play a decisive role in the potentiated chemotaxis toward PDGF-BB in a number of cell types. Finally, we explain the mechanism behind simvastatin-induced apoptosis in cancer cells and how statins interfere with TF-dependent signaling and coagulation.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 71 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 391
Tissue factor, Apoptosis, Migration, Chemotaxis, Simvastatin, Platelet Derived Growth Factor, Cell Signaling, Microparticles, Prostasomes, Trombosis, Coagulation, Prostate Cancer, Breast Cancer, Caspase-3, Caspase-8, NFkappaB, PAR2, Transactivation, Monocytes
National Category
Other Clinical Medicine
urn:nbn:se:uu:diva-9335 (URN)978-91-554-7317-4 (ISBN)
Public defence
2008-11-21, Enghoffsalen, Akademiska sjukhuset, Ingång 50, Uppsala, 09:15
Available from: 2008-10-30 Created: 2008-10-30Bibliographically approved

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