RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines
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Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.
KeywordsMultiple myeloma RANK RANKL CAM-DR Bim
This work was supported in part by a grant-in-aid for Scientific Research (C) (grant number 15K08116), grant-in-aid for Young Scientists (B) (grant number 25860071) from the Japan Society for the Promotion of Science (JSPS), and by Ministry of Education, Culture, Sports, Science, and Technology (MEXT)-Supported Program for the Strategic Reseach Foundation at Private Universities, 2014-2018 (grant number S1411037).
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Conflicts of interest
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