Format

Send to

Choose Destination
Tumour Biol. 2016 Jul;37(7):9099-110. doi: 10.1007/s13277-015-4761-8. Epub 2016 Jan 14.

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

Author information

1
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
2
Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, 631-8505, Japan.
3
Department of Surgery, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.
4
Department of Pathology, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.
5
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan. nishida@phar.kindai.ac.jp.

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.

KEYWORDS:

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

PMID:
26762414
DOI:
10.1007/s13277-015-4761-8
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center