論文 - 詳細
| RRC ID | 77791 |
|---|---|
| 著者 | Pan Y, Suzuki T, Sakai K, Hirano Y, Ikeda H, Hattori A, Dohmae N, Nishio K, Kakeya H. |
| タイトル | Bisabosqual A: A novel asparagine synthetase inhibitor suppressing the proliferation and migration of human non-small cell lung cancer A549 cells. |
| ジャーナル | Eur J Pharmacol |
| Abstract |
Asparagine synthetase (ASNS) is a crucial enzyme for the de novo biosynthesis of endogenous asparagine (Asn), and ASNS shows the positive relationship with the growth of several solid tumors. Most of ASNS inhibitors are analogs of transition-state in ASNS reaction, but their low cell permeability hinders their anticancer activity. Therefore, novel ASNS inhibitors with a new pharmacophore urgently need to be developed. In this study, we established and applied a system for in vitro screening of ASNS inhibitors, and found a promising unique bisabolane-type meroterpenoid molecule, bisabosqual A (Bis A), able to covalently modify K556 site of ASNS protein. Bis A targeted ASNS to suppress cell proliferation of human non-small cell lung cancer A549 cells and exhibited a synergistic effect with L-asparaginase (L-ASNase). Mechanistically, Bis A promoted oxidative stress and apoptosis, while inhibiting autophagy, cell migration and epithelial-mesenchymal transition (EMT), impeding cancer cell development. Moreover, Bis A induced negative feedback pathways containing the GCN2-eIF2α-ATF4, PI3K-AKT-mTORC1 and RAF-MEK-ERK axes, but combination treatment of Bis A and rapamycin/torin-1 overcame the potential drug resistance triggered by mTOR pathways. Our study demonstrates that ASNS inhibition is promising for cancer chemotherapy, and Bis A is a potential lead ASNS inhibitor for anticancer development. |
| 巻・号 | 960 |
| ページ | 176156 |
| 公開日 | 2023-12-5 |
| DOI | 10.1016/j.ejphar.2023.176156 |
| PII | S0014-2999(23)00670-2 |
| PMID | 38059445 |
| MeSH | A549 Cells Asparagine / metabolism Asparagine / pharmacology Aspartate-Ammonia Ligase* / metabolism Carcinoma, Non-Small-Cell Lung* / drug therapy Cell Line, Tumor Cell Proliferation Humans Lung Neoplasms* / drug therapy Phosphatidylinositol 3-Kinases |
| IF | 3.263 |
| 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 | |
| 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 | A549(RCB0098) HCT116(RCB2979) |