Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma
Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma
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DOI：
10.1038/leu.2014.147
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发表时间：
2015-01-01
期刊：
影响因子：
11.4
通讯作者：
Abe, M.
中科院分区：
文献类型：
--
作者：
Hiasa, M.;Teramachi, J.;Abe, M.
Pim-2激酶在多发性骨髓瘤（MM）细胞中过表达，以增强其生长和存活，并被视为MM的新治疗靶点。然而，Pim-2抑制对MM骨疾病的影响仍然未知。我们在此证明，在骨髓基质细胞和MC 3 T3-E1前成骨细胞中，在存在称为MM成骨细胞生成抑制剂的细胞因子（包括白细胞介素-3（IL-3）、IL-7、肿瘤坏死因子-α、转化生长因子-β（TGF-β）和激活素A）以及MM细胞条件培养基的情况下，Pim-2表达也上调。Pim-2的强制表达通过BMP-2废除了体外成骨细胞发生，这表明Pim-2是成骨细胞发生的负调节因子。用Pim-2短干扰RNA以及Pim抑制剂SMI-16 a治疗成功地恢复了由所有上述抑制因子和MM细胞抑制的成骨细胞生成。SMI-16 a处理增强BMP-2介导的合成代谢信号传导，同时抑制TGF-β信号传导。此外，在MM动物模型中，用新合成的噻唑烷-2，4-二酮同系物12 a-OH及其原型SMI-16 a治疗有效地防止了骨破坏，同时抑制了MM肿瘤生长。因此，Pim-2可能在MM的肿瘤进展和骨丢失中具有关键作用，并且Pim-2抑制可能成为靶向MM细胞-骨髓相互作用的重要治疗策略。
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-alpha, transforming growth factor-beta (TGF-beta) 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-beta 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.