論文 - 詳細
| RRC ID | 65485 |
|---|---|
| 著者 | Khaledian B, Taguchi A, Shin-Ya K, Kondo-Ida L, Kagaya N, Suzuki M, Kajino T, Yamaguchi T, Shimada Y, Takahashi T. |
| タイトル | Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma. |
| ジャーナル | Cancer Sci |
| Abstract |
We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in lung adenocarcinoma. ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin-like growth factor 1 receptor in part by maintaining the caveolae structure as a scaffold protein of cavin-1 and caveolin-1. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell-based FluoPPI assay detecting ROR1-cavin-1 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90α, but not with other HSP90 paralogs, HSP90β or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose- and time-dependent manner through the ubiquitin/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N-glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1-positive lung adenocarcinoma. |
| 巻・号 | 112(3) |
| ページ | 1225-1234 |
| 公開日 | 2021-3-1 |
| DOI | 10.1111/cas.14786 |
| PMID | 33370472 |
| PMC | PMC7935804 |
| MeSH | Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / pathology Antibiotics, Antineoplastic / pharmacology* Antibiotics, Antineoplastic / therapeutic use Benzoquinones / pharmacology Benzoquinones / therapeutic use Cell Line, Tumor Cell Proliferation / drug effects Drug Screening Assays, Antitumor Gene Knockdown Techniques HSP90 Heat-Shock Proteins / antagonists & inhibitors* HSP90 Heat-Shock Proteins / genetics HSP90 Heat-Shock Proteins / metabolism High-Throughput Screening Assays Humans Lactams, Macrocyclic / pharmacology Lactams, Macrocyclic / therapeutic use Lung Neoplasms / drug therapy* Lung Neoplasms / pathology Proteasome Endopeptidase Complex / metabolism Proteolysis / drug effects RNA-Binding Proteins / metabolism Receptor Tyrosine Kinase-like Orphan Receptors / metabolism* |
| IF | 4.966 |
| 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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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |