Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma
Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma
复制标题
DOI：
10.1172/jci134930
复制
发表时间：
2020-08-03
影响因子：
15.9
通讯作者：
Wang, Zhe
中科院分区：
文献类型：
--
作者：
Li, Ming-Yang;Fan, Lin-Ni;Wang, Zhe
食道鳞状细胞癌(ESCC)是最具侵袭性的癌症之一，对目前的治疗方法具有很高的耐药性。ESCC细胞亚群具有肿瘤干细胞(CSC)特性，这些特性有助于包括放射抵抗在内的治疗抵抗，但目前ESCC CSCs的分子机制尚不清楚。在这里，我们报告了核糖体S6蛋白激酶4(RSI(4))在促进ESCC的CSC特性和辐射抵抗中起着关键作用。RSK4在ESCC CSCs中高表达，并与ESCC患者的放射抵抗和生存不良有关。RSK4被发现是Delta Np63α的直接下游转录靶点，Delta Np63α是主要的p63亚型，在ESCC中经常被扩增。RSK4通过直接磷酸化Ser9处的GSK-3β来激活β-连环蛋白信号通路。在裸鼠和患者来源的异种移植模型中，药物抑制RSK4有效地降低了CSC的特性，并提高了放射敏感性。总之，我们的结果有力地表明，Delta Np63α/RSK4/GSK-3β轴在推动ESCC的CSC特性和辐射抵抗方面发挥着ICEY作用，表明RSK4是治疗ESCC的一个有前景的治疗靶点。
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 (RSI(4) 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 Delta Np63 alpha, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the beta-catenin signaling pathway through direct phosphorylation of GSK-3 beta 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 Delta Np63 alpha/RSK4/GSK-3 beta axis plays a Icey role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.