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
2008 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 122, no 2, 191-202 p.Article in journal (Refereed) Published
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.
Statins, Apoptosis, NFκB, Tissue factor, FVIIa, Cell signaling
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-97673DOI: 10.1016/j.thromres.2007.09.017ISI: 000257282500008PubMedID: 18031796OAI: oai:DiVA.org:uu-97673DiVA: diva2:172704