論文 - 詳細
| RRC ID | 59846 |
|---|---|
| 著者 | Shiba-Ishii A, Hong J, Hirokawa T, Kim Y, Nakagawa T, Sakashita S, Sakamoto N, Kozuma Y, Sato Y, Noguchi M. |
| タイトル | Stratifin Inhibits SCFFBW7 Formation and Blocks Ubiquitination of Oncoproteins during the Course of Lung Adenocarcinogenesis. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming an SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells. EXPERIMENTAL DESIGN:In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN-binding domain on SKP1. We examined expression, localization, and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549. In silico library screening and experimental validation were used for drug screening. Daily oral administration of each candidate drugs to A549-injected tumor-bearing mice was performed to evaluate their in vivo antitumor efficacy. RESULTS:Suppression of SFN upregulated the stability of SKP1 and accelerated its cytoplasm-to-nucleus translocation. Consistently, IHC analysis revealed that cytoplasmic expression of SKP1 was significantly associated with SFN positivity, tumor malignancy, and poorer patient outcome. After SFN suppression, ubiquitination of oncoproteins, including p-cyclin E1, p-c-Myc, p-c-Jun, and cleaved Notch 1, which are target proteins of SCFFBW7, was strongly induced. These results indicate that SFN-SKP1 binding results in SCFFBW7 dysfunction and allows several oncoproteins to evade ubiquitination and subsequent degradation. Because inhibition of SFN-SKP1 binding was expected to have antitumor efficacy, we next searched for candidate SFN inhibitors. Aprepitant and ticagrelor were finally selected as potential SFN inhibitors that dose dependently reduced SFN-SKP1 binding and tumor progression in vivo. CONCLUSIONS:As overexpression of SFN is detectable in most adenocarcinoma, we believe that SFN inhibitors would be novel and promising antitumor drugs for lung adenocarcinoma. |
| 巻・号 | 25(9) |
| ページ | 2809-2820 |
| 公開日 | 2019-5-1 |
| DOI | 10.1158/1078-0432.CCR-18-3631 |
| PII | 1078-0432.CCR-18-3631 |
| PMID | 30728155 |
| MeSH | 14-3-3 Proteins / genetics 14-3-3 Proteins / metabolism* Adenocarcinoma of Lung / genetics Adenocarcinoma of Lung / metabolism Adenocarcinoma of Lung / pathology* Animals Apoptosis Biomarkers, Tumor / genetics Biomarkers, Tumor / metabolism* Cell Proliferation Exoribonucleases / genetics Exoribonucleases / metabolism* Female Follow-Up Studies Gene Expression Regulation, Neoplastic Humans Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology* Mice Mice, Inbred BALB C Mice, Nude Oncogene Proteins / genetics Oncogene Proteins / metabolism* Prognosis Protein Stability S-Phase Kinase-Associated Proteins / chemistry S-Phase Kinase-Associated Proteins / genetics S-Phase Kinase-Associated Proteins / metabolism* SKP Cullin F-Box Protein Ligases / genetics SKP Cullin F-Box Protein Ligases / metabolism* Survival Rate Tumor Cells, Cultured Ubiquitin / metabolism* Ubiquitination Xenograft Model Antitumor Assays |
| IF | 8.911 |
| 引用数 | 1 |
| リソース情報 | |
| ヒト・動物細胞 | A549(RCB0098) |