RRC ID 51600
Author Tsubaki M, Takeda T, Yoshizumi M, Ueda E, Itoh T, Imano M, Satou T, Nishida S.
Title RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines.
Journal Tumour Biol
Abstract 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.
Volume 37(7)
Pages 9099-110
Published 2016-7-1
DOI 10.1007/s13277-015-4761-8
PII 10.1007/s13277-015-4761-8
PMID 26762414
MeSH ATP Binding Cassette Transporter, Subfamily B / genetics ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics Cell Adhesion / genetics* Cell Line, Tumor Drug Resistance / genetics* Gene Expression Regulation, Neoplastic / genetics Humans Low Density Lipoprotein Receptor-Related Protein-1 / genetics Multiple Myeloma / genetics* Neoplasm Proteins / genetics Protein Interaction Domains and Motifs / genetics RANK Ligand / genetics* RNA Interference / physiology Receptor Activator of Nuclear Factor-kappa B / genetics* Signal Transduction / genetics
IF 3.65
Times Cited 14
Human and Animal Cells ST2(RCB0224)