Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma

M. Hiasa, J. Teramachi, A. Oda, R. Amachi, T. Harada, S. Nakamura, H. Miki, S. Fujii, K. Kagawa, K. Watanabe, I. Endo, Y. Kuroda, T. Yoneda, D. Tsuji, M. Nakao, E. Tanaka, K. Hamada, S. Sano, K. Itoh, T. MatsumotoM. Abe

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.

Original languageEnglish
Pages (from-to)207-217
Number of pages11
JournalLeukemia
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 10 2015
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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