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

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-α, 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.

• Authors: 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 Matsumoto, M Abe
• Journal: Leukemia (Leukemia) Vol. 29 Issue 1 Pg. 207-17 (Jan 2015) ISSN: 1476-5551 [Electronic] England
• PMID: 24787487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Protein 2
• DNA Primers
• PIM2 protein, human
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases

Topics

• Base Sequence
• Bone Morphogenetic Protein 2 (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• DNA Primers
• Disease Progression
• Humans
• Multiple Myeloma (complications, drug therapy, pathology)
• Osteoblasts (cytology)
• Osteoporosis (complications, drug therapy, pathology)
• Protein Serine-Threonine Kinases (drug effects)
• Proto-Oncogene Proteins (drug effects)
• Real-Time Polymerase Chain Reaction
• Signal Transduction