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.

Bone Pain Induced by Multiple Myeloma Is Reduced by Targeting V-ATPase and ASIC3

“…JJN3 cells (5 × 10 5 ) or PBS (sham) were injected into the right tibia marrow of female C57BL/6 SCID mice (4–6 week-old) under anesthesia (32). …”

“…Bone sections were stained for TRAP activity using a TRACP & ALP double-stain Kit (Takara Bio) (32) and analyzed using Magnafire 4.1 software (Optronics) with the IX70 microscope (Olympus).…”

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

“…This up-regulation of the Pim2 gene is driven by IL6 and tumor necrosis factor (TNF) family cytokines (TNF-a, BAFF and APRIL) through signal transducer and activator of transcription 3 (STAT3) and nuclear factor kB (NK-kB) activation [51]. Treatment with Pim2 siRNA has successfully reduced MM cell proliferation [52].…”

Targeting Pim Kinases for Cancer Treatment: Opportunities and Challenges

“…Pim-1 was later found to be increased in solid tumors, including pancreatic and prostate cancer, squamous cell carcinoma, gastric carcinoma, colorectal carcinoma, liver carcinoma [1,15], bladder carcinoma [76] and liposarcoma [77]. Pim-2 is upregulated in various leukemia, lymphomas, myeloma, prostate and liver cancer [78][79][80][81]. Overexpression of Pim-3 is often found in malignant lesions of endoderm-derived organs, liver, pancreas, colon and stomach and Ewing's sarcoma [16].…”