文献类型：期刊文献

英文题名：Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma

作者：Li, Ming-Yang[1,2];Fan, Lin-Ni[1,2];Han, Dong-Hui[3];Yu, Zhou[1,2];Ma, Jing[1,2];Liu, Yi-Xiong[1,2];Li, Pei-Feng[1,2];Zhao, Dan-Hui[1,2];Chai, Jia[1,2];Jiang, Lei[4];Li, Shi-Liang[4];Xiao, Juan-Juan[5];Duan, Qiu-Hong[6];Ye, Jing[1,2];Shi, Mei[7];Nie, Yong-Zhan[8];Wu, Kai-Chun[8];Liao, Dezhong Joshua[9];Shi, Yu[10,11];Wang, Yan[10,11];Yan, Qing-Guo[1,2];Guo, Shuang-Ping[1,2];Bian, Xiu-Wu[10,11];Zhu, Feng[5,6];Zhang, Jian[12,13];Wang, Zhe[1,2]

机构：[1]Fourth Mil Med Univ, Xijing Hosp, Dept Pathol, State Key Lab Canc Biol, 169 Changle West Rd, Xian 710032, Peoples R China;[2]Fourth Mil Med Univ, Sch Basic Med, 169 Changle West Rd, Xian 710032, Peoples R China;[3]Fourth Mil Med Univ, Xijing Hosp, Dept Urol, Xian, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[5]Guilin Med Univ, Canc Res Inst, Affiliated Hosp, 15 Lequn Rd, Guilin 541000, Peoples R China;[6]Huazhong Univ Sci & Technol, Sch Basic Med, Dept Biochem & Mol Biol, Wuhan, Peoples R China;[7]Fourth Mil Med Univ, Xijing Hosp, Dept Radiat Oncol, Natl Clin Res Ctr Digest Dis, Xian, Peoples R China;[8]Fourth Mil Med Univ, Xijing Hosp, Natl Clin Res Ctr Digest Dis, State Key Lab Canc Biol, Xian, Peoples R China;[9]Guizhou Univ Tradit Chinese Med, Hosp 2, Dept Pathol, Guiyang, Peoples R China;[10]Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing, Peoples R China;[11]Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China;[12]Fourth Mil Med Univ, Dept Biochem & Mol Biol, State Key Lab Canc Biol, Sch Basic Med, 169 Changle West Rd, Xian 710032, Peoples R China;[13]Fourth Mil Med Univ, Sch Pharm, Key Lab Gastrointestinal Pharmacol Chinese Mat Me, State Adm Tradit Chinese Med, 169 Changle West Rd, Xian 710032, Peoples R China

年份：2020

卷号：130

期号：8

起止页码：4301

外文期刊名：JOURNAL OF CLINICAL INVESTIGATION

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000579356100002)】；

基金：This work was supported by grants from the National Natural Science Foundation of China (81272651, 81570180, 81421003, 81770523, and 81472402) and the State Key Laboratory of Cancer Biology (CBSKL2014Z07). We thank Deng-Xu Tan (Laboratory Animal Center, Fourth Military Medical University) for assistance in establishing the PDX models. We thank Pei-Pei Xue and Ling Zou (Department of Biochemistry and Molecular Biology, Huazhong University of Science and Technology) for help with in vitro kinase analyses. We thank Hui-Ping Liu (Department of Pharmacology, Feinberg School of Medicine, Northwestern University) for the important suggestions for this study.

语种：英文

摘要：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.