title: RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines.
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.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Yoshizumi
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Ueda
authors.affiliation: Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, 631-8505, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Surgery, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan. nishida@phar.kindai.ac.jp.
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D004351:Drug Resistance / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009363:Neoplasm Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human
keywords: Bim; CAM-DR; Multiple myeloma; RANK; RANKL