Tumor Biology

, Volume 37, Issue 7, pp 9099–9110 | Cite as

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

  • Masanobu Tsubaki
  • Tomoya Takeda
  • Misako Yoshizumi
  • Emi Ueda
  • Tatsuki Itoh
  • Motohiro Imano
  • Takao Satou
  • Shozo NishidaEmail author
Original Article


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.


Multiple 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).

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2015_4761_MOESM1_ESM.pdf (430 kb)
ESM 1 (PDF 429 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Masanobu Tsubaki
    • 1
  • Tomoya Takeda
    • 1
  • Misako Yoshizumi
    • 1
  • Emi Ueda
    • 1
  • Tatsuki Itoh
    • 2
  • Motohiro Imano
    • 3
  • Takao Satou
    • 4
  • Shozo Nishida
    • 1
    Email author
  1. 1.Division of PharmacotherapyKinki University School of PharmacyKowakaeJapan
  2. 2.Department of Food Science and NutritionKinki University School of AgricultureNaraJapan
  3. 3.Department of SurgeryKinki University School of MedicineOsakasayamaJapan
  4. 4.Department of PathologyKinki University School of MedicineOsakasayamaJapan

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