Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells.
Bone morphogenetic proteins (BMPs) can be isolated from organic bone matrix and are able to initiate de novo cartilage and bone formation. Here it is shown that BMP-4 inhibited DNA synthesis in a dose-dependent manner in 3 IL-6-dependent multiple myeloma (MM) cell lines (OH-2, IH-1, and ANBL-6). In contrast, no effect on DNA synthesis was observed in 3 IL-6-independent MM cell lines (JJN-3, U266, and RPMI 8226). BMP-4 induced cell cycle growth arrest in the G(0)/G(1) phase in OH-2 and ANBL-6 cells but not in IH-1 cells. BMP-4 induced apoptosis in OH-2 and IH-1 cells, but not significantly in ANBL-6 cells. Furthermore, BMP-4 induced apoptosis in freshly isolated MM cells from 4 of 13 patients. In the OH-2 and ANBL-6 cell lines and in a patient sample, immunoblotting showed that BMP-4 down-regulated IL-6-induced tyrosine phosphorylation of Stat3, suggesting a mechanism for the apparent antagonism between IL-6 and BMP-4. BMP-4 or analogues may be attractive therapeutic agents in MM because of possible beneficial effects on both tumor burden and bone disease.
Hjertner
O
O
Institute of Cancer Research and Molecular Biology, and the Section of Hematology, Institute of Environmental Medicine, Norwegian University of Science and Technology, Trondheim, Norway. oyvind.hjertner@medisin.ntnu.no
Hjorth-Hansen
H
H
Börset
M
M
Seidel
C
C
Waage
A
A
Sundan
A
A
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology* / Q000502:physiology*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology* / Q000503:physiopathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C525809:BMP4 protein, human; C494086:STAT3 protein, human