Functional significance of novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) for human myeloma cell growth and survival.
Cytokines of the gp130 family, particularly interleukin 6 (IL-6), play a central role in the growth and survival of malignant plasma cells. Recently, novel neurotrophin-1 (NNT-1)/B cell-stimulating factor-3 (BSF-3), also reported as cardiotrophin-like cytokine (CLC), was identified as a cytokine belonging to the gp130 family. BSF-3, similar to IL-6, exerts regulatory effects on normal B cell functions, but its functional significance in haematological malignancies has not been defined. The purpose of this study was to evaluate the biological effects and signalling pathways that are induced by BSF-3 in malignant plasma cells. Recombinant human BSF-3 was found to have growth stimulatory activity on plasmacytoma cell lines and primary tumour cells. In addition, BSF-3 was able to protect from Dexamethasone (Dex)-induced apoptosis. BSF-3 stimulated cell growth could not be inhibited by neutralizing anti-IL-6 or anti-IL-6 receptor antibodies, but was abrogated by anti-gp130 antibodies. In INA-6.Tu11 cells, a subline of the IL-6-dependent human plasma cell line INA-6 expressing gp130 and the receptor for leukaemia inhibitory factor (LIF), stimulation with BSF-3 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). AG490, an inhibitor of Janus kinases, decreased BSF-3 induced cell growth in a dose-dependent manner. This correlated with a reduction of STAT3 phosphorylation levels, while p44/42 mitogen-activated protein kinase (MAPK) phosphorylation was not affected. In conclusion, BSF-3 is a novel myeloma growth and survival factor with a potential role in the pathophysiology of the disease.
Burger
Renate
R
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Bakker
Frank
F
Guenther
Andreas
A
Baum
Wolfgang
W
Schmidt-Arras
Dirk
D
Hideshima
Teru
T
Tai
Yu-Tzu
YT
Shringarpure
Reshma
R
Catley
Laurence
L
Senaldi
Giorgio
G
Gramatzki
Martin
M
Anderson
Kenneth C
KC
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494199:IL6ST protein, human; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C121169:cardiotrophin-like cytokine; D050822:Cytokine Receptor gp130; D003907:Dexamethasone