Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma
| Autor: | Jing Ye, Dong-Hui Han, Mingyang Li, Danhui Zhao, Kaichun Wu, Yongzhan Nie, Yan Wang, Peifeng Li, Qingguo Yan, Shuangping Guo, Linni Fan, Yu Shi, Zhe Wang, Jia Chai, Lei Jiang, Jian Zhang, Qiuhong Duan, Zhou Yu, Dezhong Joshua Liao, Juanjuan Xiao, Mei Shi, Feng Zhu, Xiu-Wu Bian, Jing Ma, Shi-Liang Li, Yixiong Liu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Esophageal Neoplasms Cell Radiation Tolerance Ribosomal Protein S6 Kinases 90-kDa Gene Expression Regulation Enzymologic 03 medical and health sciences Mice 0302 clinical medicine Nude mouse Radioresistance medicine Animals Humans Radiosensitivity Protein kinase A neoplasms biology Tumor Suppressor Proteins Cancer General Medicine biology.organism_classification medicine.disease Xenograft Model Antitumor Assays digestive system diseases Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure HEK293 Cells 030220 oncology & carcinogenesis Cancer research Phosphorylation Esophageal Squamous Cell Carcinoma Signal transduction Signal Transduction Transcription Factors Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|