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Myeloma

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

Leukemia volume 29, pages 207–217 (2015)Cite this article

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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.

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Acknowledgements

This work was supported in part by a Grants-in-aid for Scientific Research (C) (23591390) from the Ministry of Education, Science, Sport, and Culture of Japan, a National Cancer Center Research and Development Fund (21-8-5) from the Ministry of Health, Labor and Welfare of Japan, and A-STEP from Japan Science and Technology Agency (AS242Z02068Q) to MA, and a Japan Leukemia Research Fund, IMF Japan Aki Horinouchi Research Grant, and a Grant-in-Aid for Scientific Research (21792077, 23659946 and 25463087) from the Ministry of Education, Science, Sport and Culture of Japan to MH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    M Hiasa, A Oda, T Harada, S Nakamura, H Miki, S Fujii, K Kagawa, I Endo, T Matsumoto & M Abe

  2. Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    M Hiasa & K Hamada

  3. Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    M Hiasa, R Amachi, K Watanabe & E Tanaka

  4. Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    J Teramachi

  5. Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan

    Y Kuroda

  6. Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN, USA

    T Yoneda

  7. Department of Medicinal Biotechnology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    D Tsuji & K Itoh

  8. Department of Molecular Medicinal Chemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    M Nakao & S Sano

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  1. M Hiasa
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Correspondence to M Abe.

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Hiasa, M., Teramachi, J., Oda, A. et al. Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. Leukemia 29, 207–217 (2015). https://doi.org/10.1038/leu.2014.147

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