RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines

作者：Tsubaki Masanobu; Takeda Tomoya; Yoshizumi Misako; Ueda Emi; Itoh Tatsuki; Imano Motohiro; Satou Takao; Nishida Shozo^*

来源：Tumor Biology, 2016, 37(7): 9099-9110.

DOI：10.1007/s13277-015-4761-8

• Multiple myeloma
• RANK
• RANKL
• CAM-DR
• Bim

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-kappa B (NF-kappa B) (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.

• 出版日期2016-7