論文 - 詳細
| RRC ID | 56026 |
|---|---|
| 著者 | Nam AR, Kim JW, Park JE, Bang JH, Jin MH, Oh DY, Bang YJ. |
| タイトル | Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer. |
| ジャーナル | Cancer Res Treat |
| Abstract |
PURPOSE:Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied. MATERIALS AND METHODS:We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC. RESULTS:Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and p27 expression. CONCLUSION:Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations. |
| 巻・号 | 51(3) |
| ページ | 886-900 |
| 公開日 | 2019-7-1 |
| DOI | 10.4143/crt.2018.375 |
| PII | crt.2018.375 |
| PMID | 30282449 |
| PMC | PMC6639236 |
| MeSH | Animals Antineoplastic Agents / administration & dosage* Antineoplastic Agents / pharmacology Biliary Tract Neoplasms / drug therapy Biliary Tract Neoplasms / genetics Biliary Tract Neoplasms / metabolism* COP9 Signalosome Complex / antagonists & inhibitors COP9 Signalosome Complex / genetics* COP9 Signalosome Complex / metabolism* Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Cell Survival / drug effects Cisplatin / administration & dosage* Cisplatin / pharmacology Cyclin-Dependent Kinase Inhibitor p27 / metabolism Drug Synergism Female Gene Expression Regulation, Neoplastic / drug effects Humans Intracellular Signaling Peptides and Proteins / antagonists & inhibitors Intracellular Signaling Peptides and Proteins / genetics* Intracellular Signaling Peptides and Proteins / metabolism* Mice PTEN Phosphohydrolase / chemistry PTEN Phosphohydrolase / metabolism Peptide Hydrolases / genetics* Peptide Hydrolases / metabolism* Protein Stability / drug effects RNA, Small Interfering / administration & dosage RNA, Small Interfering / pharmacology Up-Regulation / drug effects Xenograft Model Antitumor Assays |
| IF | 3.363 |
| 引用数 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) TFK-1(RCB2537) |