State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
J Clin Invest. 2020 Aug 3;130(8):4301-4319. doi: 10.1172/JCI134930.
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.
食管鳞状细胞癌（ESCC）是最具侵袭性的癌症之一，对目前的治疗方法高度耐药。ESCC 中存在一小部分具有癌症干细胞样细胞（CSC）特性的细胞，这些特性有助于产生治疗抵抗性，包括放射抵抗性，但 ESCC CSCs 中的分子机制目前尚不清楚。在这里，我们报告核糖体 S6 蛋白激酶 4（RSK4）在促进 ESCC 的 CSC 特性和放射抵抗性方面发挥着关键作用。RSK4 在 ESCC CSCs 中高度表达，与 ESCC 患者的放射抵抗性和预后不良相关。研究发现，RSK4 是 ΔNp63α（主要的 p63 同工型）的直接下游转录靶标，而 ΔNp63α 在 ESCC 中经常扩增。RSK4 通过直接磷酸化 GSK-3β 上的 Ser9 激活 β-catenin 信号通路。RSK4 的药理学抑制作用可有效降低裸鼠和患者来源异种移植模型中的 CSC 特性并提高放射敏感性。综上所述，我们的研究结果强烈表明，ΔNp63α/RSK4/GSK-3β 轴在驱动 ESCC 的 CSC 特性和放射抵抗性方面发挥着关键作用，这表明 RSK4 是治疗 ESCC 的一个有前途的治疗靶点。
