Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma

Ming Yang Li; Lin Ni Fan; Dong Hui Han; Zhou Yu; Jing Ma; Yi Xiong Liu; Pei Feng Li; Dan Hui Zhao; Jia Chai; Lei Jiang; Shi Liang Li; Juan Juan Xiao; Qiu Hong Duan; Jing Ye; Mei Shi; Yong Zhan Nie; Kai Chun Wu; Dezhong Joshua Liao; Yu Shi; Yan Wang; Qing Guo Yan; Shuang Ping Guo; Xiu Wu Bian; Feng Zhu; Jian Zhang; Zhe Wang

doi:10.1172/JCI134930

Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma

Ming Yang Li
, Lin Ni Fan
, Dong Hui Han
, Zhou Yu
, Jing Ma
, Yi Xiong Liu
, Pei Feng Li
, Dan Hui Zhao
, Jia Chai
, Lei Jiang
, Shi Liang Li
, Juan Juan Xiao
, Qiu Hong Duan
, Jing Ye
, Mei Shi
, Yong Zhan Nie
, Kai Chun Wu
, Dezhong Joshua Liao
, Yu Shi
, Yan Wang

Qing Guo Yan, Shuang Ping Guo, Xiu Wu Bian, Feng Zhu^*, Jian Zhang^*, Zhe Wang^*

^*Corresponding author for this work

Xijing Hospital
East China University of Science and Technology
Guilin Medical College
Huazhong University of Science and Technology
Guizhou University of Traditional Chinese Medicine
Army Medical University
Air Force Medical University

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4301-4319
Number of pages	19
Journal	Journal of Clinical Investigation
Volume	140
Issue number	8
DOIs	https://doi.org/10.1172/JCI134930
State	Published - 3 Aug 2020
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1172/JCI134930

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Li, M. Y., Fan, L. N., Han, D. H., Yu, Z., Ma, J., Liu, Y. X., Li, P. F., Zhao, D. H., Chai, J., Jiang, L., Li, S. L., Xiao, J. J., Duan, Q. H., Ye, J., Shi, M., Nie, Y. Z., Wu, K. C., Liao, D. J., Shi, Y., ... Wang, Z. (2020). Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma. Journal of Clinical Investigation, 140(8), 4301-4319. https://doi.org/10.1172/JCI134930

@article{a118ec2debbe43eaa6b90a131471a2cf,

title = "Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma",

abstract = "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.",

author = "Li, \{Ming Yang\} and Fan, \{Lin Ni\} and Han, \{Dong Hui\} and Zhou Yu and Jing Ma and Liu, \{Yi Xiong\} and Li, \{Pei Feng\} and Zhao, \{Dan Hui\} and Jia Chai and Lei Jiang and Li, \{Shi Liang\} and Xiao, \{Juan Juan\} and Duan, \{Qiu Hong\} and Jing Ye and Mei Shi and Nie, \{Yong Zhan\} and Wu, \{Kai Chun\} and Liao, \{Dezhong Joshua\} and Yu Shi and Yan Wang and Yan, \{Qing Guo\} and Guo, \{Shuang Ping\} and Bian, \{Xiu Wu\} and Feng Zhu and Jian Zhang and Zhe Wang",

note = "Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = aug,

day = "3",

doi = "10.1172/JCI134930",

language = "英语",

volume = "140",

pages = "4301--4319",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "8",

}

Li, MY, Fan, LN, Han, DH, Yu, Z, Ma, J, Liu, YX, Li, PF, Zhao, DH, Chai, J, Jiang, L, Li, SL, Xiao, JJ, Duan, QH, Ye, J, Shi, M, Nie, YZ, Wu, KC, Liao, DJ, Shi, Y, Wang, Y, Yan, QG, Guo, SP, Bian, XW, Zhu, F, Zhang, J & Wang, Z 2020, 'Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma', Journal of Clinical Investigation, vol. 140, no. 8, pp. 4301-4319. https://doi.org/10.1172/JCI134930

TY - JOUR

T1 - Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma

AU - Li, Ming Yang

AU - Fan, Lin Ni

AU - Han, Dong Hui

AU - Yu, Zhou

AU - Ma, Jing

AU - Liu, Yi Xiong

AU - Li, Pei Feng

AU - Zhao, Dan Hui

AU - Chai, Jia

AU - Jiang, Lei

AU - Li, Shi Liang

AU - Xiao, Juan Juan

AU - Duan, Qiu Hong

AU - Ye, Jing

AU - Shi, Mei

AU - Nie, Yong Zhan

AU - Wu, Kai Chun

AU - Liao, Dezhong Joshua

AU - Shi, Yu

AU - Wang, Yan

AU - Yan, Qing Guo

AU - Guo, Shuang Ping

AU - Bian, Xiu Wu

AU - Zhu, Feng

AU - Zhang, Jian

AU - Wang, Zhe

PY - 2020/8/3

Y1 - 2020/8/3

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85089127938

U2 - 10.1172/JCI134930

DO - 10.1172/JCI134930

M3 - 文章

C2 - 32396532

AN - SCOPUS:85089127938

SN - 0021-9738

VL - 140

SP - 4301

EP - 4319

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 8

ER -

Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma

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