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

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Tumor Biology

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.

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Acknowledgments

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).

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Authors and Affiliations

  1. Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan

    Masanobu Tsubaki, Tomoya Takeda, Misako Yoshizumi, Emi Ueda & Shozo Nishida

  2. Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, 631-8505, Japan

    Tatsuki Itoh

  3. Department of Surgery, Kinki University School of Medicine, Osakasayama, 589-8511, Japan

    Motohiro Imano

  4. Department of Pathology, Kinki University School of Medicine, Osakasayama, 589-8511, Japan

    Takao Satou

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  1. Masanobu Tsubaki
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  2. Tomoya Takeda
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  3. Misako Yoshizumi
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Correspondence to Shozo Nishida.

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Tsubaki, M., Takeda, T., Yoshizumi, M. et al. RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. Tumor Biol. 37, 9099–9110 (2016). https://doi.org/10.1007/s13277-015-4761-8

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  • DOI: https://doi.org/10.1007/s13277-015-4761-8

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