| Autor: |
Lagler C; Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, Wuerzburg, Germany., El-Mesery M; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Kübler AC; Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, Wuerzburg, Germany., Müller-Richter UDA; Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, Wuerzburg, Germany., Stühmer T; Comprehensive Cancer Center Mainfranken (CCCMF), University Hospital of Wuerzburg, Wuerzburg, Germany., Nickel J; Chair Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.; Fraunhofer IGB, Translational Center Wuerzburg 'Regenerative therapies in oncology and musculoskeletal diseases', Wuerzburg, Germany., Müller TD; Julius-von-Sachs-Institute, Department of Molecular Plant Physiology and Biophysics, University of Wuerzburg, Wuerzburg, Germany., Wajant H; Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany., Seher A; Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, Wuerzburg, Germany. |
| Abstrakt: |
Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2. |
