Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells.
Previously, bone morphogenetic protein (BMP)-2 and -4 have been shown to inhibit proliferation and induce apoptosis in human myeloma cells. BMP-2 and -4 belong to a subgroup of BMPs using the BMP receptors Alk-3 or -6. In this study, we examined the effects on human myeloma cells of BMP-6 and -7, members of a different BMP subgroup, which mainly utilize Alk-2 as their receptor. All cell lines examined expressed mRNA for the BMP-6 and -7 receptor Alk-2. We did not detect transcripts for the BMP-2 and -4 receptors Alk-3 or Alk-6 in INA-6 and RPMI-8226 cells by RT-PCR. Accordingly, the intracellular signalling molecules Smad-1, -5 and -8 were not phosphorylated by BMP-4 in INA-6 and RPMI-8226 cells. The expression patterns of various BMP receptors in the myeloma cell lines explained the differences in responses to the various BMPs. Alk-2-expressing cell lines responded with growth inhibition and apoptosis to BMP-6 and -7, whereas cell lines lacking both Alk-3 and -6 were resistant to BMP-4. Soluble Alk-3 and -6 were able to neutralize the BMP-4 effects in BMP-4-responsive cell lines. All BMPs reduced viability in more than 70% of purified primary myeloma cell samples. BMPs have intriguing antitumor effects in vitro. Importantly, myeloma cells not responsive to BMP-2 and -4 may still be sensitive to BMP-6 or -7. It is possible that therapeutic use of BMP or BMP analogues could have an impact on both myeloma bone disease and myeloma cell growth.
Ro
Torstein Baade
TB
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7489, Norway. torstein.ro@medisin.ntnu.no
Holt
Randi Utne
RU
Brenne
Anne-Tove
AT
Hjorth-Hansen
Henrik
H
Waage
Anders
A
Hjertner
Oyvind
O
Sundan
Anders
A
Borset
Magne
M
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2; D055417:Bone Morphogenetic Protein 5; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C525718:BMP2 protein, human; C525814:BMP5 protein, human; C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055417:Bone Morphogenetic Protein 5; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta