Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3

C. Kawamura, M. Kizaki, K. Yamato, H. Uchida, Y. Fukuchi, Y. Hattori, T. Koseki, T. Nishihara, Y. Ikeda

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-β superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21(CIP1/WAF1) and p27(KIP1)) and caused hypophosphorylation of retino-blastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-X(L); however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-x(L) and by cell-cycle arrest through the up-regulation of p21(CIP1/WAF1) and p27(KIP1) and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. 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. (C) 2000 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)2005-2011
Number of pages7
JournalBlood
Volume96
Issue number6
Publication statusPublished - 2000 Sep 15

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kawamura, C., Kizaki, M., Yamato, K., Uchida, H., Fukuchi, Y., Hattori, Y., Koseki, T., Nishihara, T., & Ikeda, Y. (2000). Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood, 96(6), 2005-2011.