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Leukemia ; 29(1): 207-17, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24787487

RESUMO

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-ß (TGF-ß) 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-ß 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.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Osteoporose/tratamento farmacológico , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Sequência de Bases , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Primers do DNA , Progressão da Doença , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Osteoblastos/citologia , Osteoporose/complicações , Osteoporose/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
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