RRC ID 60130
Author Mashimo K, Tsubaki M, Takeda T, Asano R, Jinushi M, Imano M, Satou T, Sakaguchi K, Nishida S.
Title RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells.
Journal Clin Exp Med
Abstract 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.
Volume 19(1)
Pages 133-141
Published 2019-2-1
DOI 10.1007/s10238-018-0531-4
PII 10.1007/s10238-018-0531-4
PMID 30291461
MeSH Antineoplastic Agents / pharmacology* Bcl-2-Like Protein 11 / metabolism* CSK Tyrosine-Protein Kinase Cell Line, Tumor Dasatinib / pharmacology* Drug Resistance, Neoplasm* Gene Expression Regulation Gene Regulatory Networks Humans Multiple Myeloma / pathology* Protein Kinase Inhibitors / pharmacology RANK Ligand / metabolism* Receptor Activator of Nuclear Factor-kappa B / metabolism src-Family Kinases / metabolism*
IF 2.642
Times Cited 3
Human and Animal Cells ST2(RCB0224)