Journal
LEUKEMIA
Volume 25, Issue 7, Pages 1182-1188Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2011.60
Keywords
Pim-2; myeloma; bone marrow stromal cell; osteoclast; IL-6
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Funding
- Ministry of Education, Culture, Science and Sports of Japan
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [23591390, 23659946] Funding Source: KAKEN
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Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNF alpha, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-kappa B pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment. Leukemia (2011) 25, 1182-1188; doi:10.1038/leu.2011.60; published online 8 April 2011
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