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Leukemia. 2015 Jan;29(1):207-17. doi: 10.1038/leu.2014.147. Epub 2014 May 2.

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

Author information

1
1] Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [2] Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [3] Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
2
Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
3
Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
4
Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
5
Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
6
Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN, USA.
7
Department of Medicinal Biotechnology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
8
Department of Molecular Medicinal Chemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
9
Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.

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.

PMID:
24787487
DOI:
10.1038/leu.2014.147
[Indexed for MEDLINE]
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