In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway.
The interleukin 6/glycoprotein 130/signal transducer and activator of transcription 3 (IL-6/gp130/STAT3) pathway has been reported to play an important role in the pathogenesis of multiple myeloma (MM) and for survival of MM cells. However, most data concerning the role of IL-6 and IL-6-triggered signaling pathways were obtained from experiments performed with MM cell lines and without considering the bone marrow microenvironment. Thus, the precise role of IL-6 and its intracellular signaling pathways for survival of human MM cells is still unclear. Here we show that treatment of human MM cells (IL-6-dependent MM cell line INA-6 and primary MM cells) with the IL-6 receptor antagonist Sant7 or with an anti-gp130 monoclonal antibody (mAb) induced apoptosis if the cells were cultured in the absence of bone marrow stromal cells (BMSCs). In contrast, apoptosis could not be observed if the MM cells were cocultured with BMSCs. The analysis of intracellular pathways revealed that Sant7 and anti-gp130 mAb were effectively inhibiting the phosphorylation of gp130 and STAT3 in the absence and presence of BMSCs, whereas ERK1 and ERK2 (ERK1,2) phosphorylation was only slightly affected. In contrast, treatment with the farnesyl transferase inhibitor, FPT III, induced apoptosis in MM cells in the absence or presence of BMSCs and led to a complete inhibition of the Ras/mitogen-activated protein kinase pathway. These observations indicate that the IL-6/gp130/STAT3 pathway is not essential for survival of human myeloma cells if they are grown in the presence of cells from the bone marrow microenvironment. Furthermore, we provide evidence that farnesyl transferase inhibitors might be useful for the development of novel therapeutic strategies for the treatment of MM.
Chatterjee
Manik
M
Department of Hematology, Oncology, and Tumorimmunology, Robert-Rössle Cancer Center at the Max-Delbrück-Center for Molecular Medicine, Charité, Humboldt University Berlin, Campus Berlin-Buch, Linderberger Weg 80, D-13122 Berlin, Germany.
Hönemann
Dirk
D
Lentzsch
Suzanne
S
Bommert
Kurt
K
Sers
Christine
C
Herrmann
Pia
P
Mathas
Stephan
S
Dörken
Bernd
B
Bargou
Ralf C
RC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D002470:Cell Survival; D018920:Coculture Techniques; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D015850:Interleukin-6 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D063065:Organophosphonates / Q000494:pharmacology; D010766:Phosphorylation; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D063065:Organophosphonates; D019947:Receptors, Interleukin-6; C432252:SANT-7; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases