論文 - 詳細
| RRC ID | 60130 |
|---|---|
| 著者 | Mashimo K, Tsubaki M, Takeda T, Asano R, Jinushi M, Imano M, Satou T, Sakaguchi K, Nishida S. |
| タイトル | RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells. |
| ジャーナル | 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. |
| 巻・号 | 19(1) |
| ページ | 133-141 |
| 公開日 | 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 |
| 引用数 | 3 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |