論文 - 詳細
| RRC ID | 58862 |
|---|---|
| 著者 | Yu X, Gao F, Li W, Zhou L, Liu W, Li M. |
| タイトル | Formononetin inhibits tumor growth by suppression of EGFR-Akt-Mcl-1 axis in non-small cell lung cancer. |
| ジャーナル | J Exp Clin Cancer Res |
| Abstract |
BACKGROUND:Epidermal growth factor receptor (EGFR) activating mutations play crucial roles in the tumorigenesis of human non-small cell lung cancer (NSCLC). The mechanism regarding how EGFR signaling regulates myeloid cell leukemia sequence 1 (Mcl-1) protein stability and ubiquitination remains undefined. METHODS:MTS assay was used for natural product library screening. The effect of formononetin (Formo) on NSCLC cells was determined by MTS assay and soft agar assay. Molecular modeling was performed to analyze the potential different binding modes between Formo and EGFR WT or mutants. Mcl-1 protein level and the inhibitory effect of Formo on EGFR signaling were examined by immunoblot, in vitro kinase assay, in vitro pulldown and ATP competition assays, co-immunoprecipitation assay, ubiquitination analysis, in vivo xenograft model, and immunohistochemical staining. RESULTS:Formo was identified as an EGFR inhibitor by a 98 commercially available natural product screening. Formo suppresses WT and mutant EGFR kinases activity in vitro, ex vivo, and in vivo. Molecular modeling indicates that Formo docks into the ATP-binding pocket of both WT and mutant EGFR. Formo inhibits EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells. Treatment with Formo enhances the interaction between Mcl-1 and SCFFbw7, which eventually promotes Mcl-1 ubiquitination and degradation. Depletion of either GSK3β or SCFFbw7 compromised Formo-induced Mcl-1 downregulation. Finally, Formo inhibits the in vivo tumor growth in a xenograft mouse model. CONCLUSION:This study highlights the importance of promoting ubiquitination-dependent Mcl-1 turnover might be an alternative strategy to enhance the anti-tumor efficacy of EGFR-TKI. |
| 巻・号 | 39(1) |
| ページ | 62 |
| 公開日 | 2020-4-10 |
| DOI | 10.1186/s13046-020-01566-2 |
| PII | 10.1186/s13046-020-01566-2 |
| PMID | 32276600 |
| PMC | PMC7146989 |
| MeSH | Animals Carcinoma, Non-Small-Cell Lung / drug therapy* Cell Line, Tumor ErbB Receptors / drug effects* Female Humans Isoflavones / pharmacology Isoflavones / therapeutic use* Lung Neoplasms / drug therapy* Mice Mice, Nude Models, Molecular Myeloid Cell Leukemia Sequence 1 Protein / drug effects* Phytoestrogens / pharmacology Phytoestrogens / therapeutic use* |
| IF | 5.646 |
| 引用数 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3 |