Clinical and Experimental Medicine

, Volume 19, Issue 1, pp 133–141 | Cite as

RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells

  • Keiji Mashimo
  • Masanobu Tsubaki
  • Tomoya Takeda
  • Ryota Asano
  • Minami Jinushi
  • Motohiro Imano
  • Takao Satou
  • Katsuhiko Sakaguchi
  • Shozo NishidaEmail author
Original Article


The survival and growth of multiple myeloma (MM) cells are facilitated by cell–cell interactions with bone marrow stromal cells and the bone marrow microenvironment. These interactions induce de novo drug resistance known as cell adhesion-mediated drug resistance. Our previous results recently revealed that the receptor activator of NF-κB (RANK) ligand (RANKL), which is expressed by bone marrow stromal cells, contributes to anti-cancer drug resistance through the activation of various signaling molecules and suppression of Bim expression in RANK-expressing MM cells. However, the detailed mechanisms underlying RANKL-induced drug resistance remain uncharacterized. In the present study, we investigated the mechanism of RANKL-induced drug resistance in RANK-expressing MM cell lines. We found treatment of MM cells with RANKL-induced c-Src phosphorylation and activation of the downstream signaling molecules Akt, mTOR, STAT3, JNK, and NF-κB. In addition, treatment with dasatinib, a c-Src inhibitor, overcame RANKL- and bone marrow stromal cell-induced drug resistance to adriamycin, vincristine, dexamethasone, and melphalan by suppressing c-Src, Akt, mTOR, STAT3, JNK, and NF-κB activation and enhancing expression of Bim. Overall, RANKL- and bone marrow stromal cell-induced drug resistance correlated with the activation of c-Src signaling pathways, which caused a decrease in Bim expression. Dasatinib treatment of RANK-expressing MM cells re-sensitized them to anti-cancer drugs. Therefore, inhibition of c-Src may be a new therapeutic approach for overcoming RANKL-induced drug resistance in patients with MM.


Multiple myeloma RANK RANKL Src Drug resistance 



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 16K18965) 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 Research Foundation at Private Universities, 2014-2018 (Grant number S1411037).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10238_2018_531_MOESM1_ESM.pdf (31 kb)
Supplementary material 1 (PDF 31 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Division of Pharmacotherapy, Faculty of PharmacyKindai UniversityHigashi-OsakaJapan
  2. 2.Department of PharmacyJapanese Red Cross Society Wakayama Medical CenterWakayamaJapan
  3. 3.Department of Surgery, Faculty of MedicineKindai UniversityOsakasayamaJapan
  4. 4.Department of Pathology, Faculty of MedicineKindai UniversityOsakasayamaJapan

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