Anti-myeloma activity of members of the TGF-β family with induction of growth arrest and apoptosis^*

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Bone morphogenetic proteins (BMPs) , members of the transforming growth factor (TGF)-β super family, are multifunctional cytokines. We show in this study that BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPM1 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 ceHs), but also in primary samples from 6 patients with multiple myeloma. BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells, which was associated with up-regulation of cyclin-dependent kinase inhibitors [p21^<CIP1/WAP1> (p21) and p27^<Kip1>] , hypophosphorylation of retinoblastoma (Rb) protein and down-regulation of Bc1-X_L, an anti-apoptotic molecule. Analysis of p21 promoter in HS-72 mouse plasmacytic cells revealed that BMP-2 induced expression of p21 at the level of transcription and that a 29-base pair <b) region of the p21 promoter (-1928/-1900 relative to the TATA box) , conserved between mice and humans, contained a binding sequence for Smad4 and Smad1 and was respons … More ible for activation of the promoter by BMP-2.We investigated the effects of increased level of p21 on cell cycle and viability using an ecdysone-inducible p21 expression clones of HS-72 cells. Ponasterone A (an analog of ecdysone)-induced accumulation of p21 resulted in the cell cycle arrest in the G1 phase as was observed in BMP-2-treated HS-72 cells. Increased p21 did not cause apoptotic cell death by 48 h after ponasterone A treatment, but initiated cell death after 4 days exposure. These results suggested that expression of p21 is responsible for BMP-2-induced G1 arrest, but not for BMP-2-induced apoptosis and that sustained expression of p21 decreases cell viability through apoptotic process.From these observation, we conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients. Less