Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells

	Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells
	Cui, Can 1,2; Pan, Yuting 1,2; Zhang, Chengqian3 ; Zhu, Darong 1,2; Xuan, Ying 1,2; Hao, Piliang3 ; Ke, Xisong 1,2; Zhou, Xianglian 1,2; Qu, Yi 1,2
	2022
发表期刊	AMERICAN JOURNAL OF CANCER RESEARCH (IF:3.6[JCR-2023],4.5[5-Year])
ISSN	2156-6976
卷号	12 期号:6
发表状态	已发表
摘要	Syndecan-4 (SDC4) is a single-pass transmembrane glycoprotein implicated in a variety of oncogenic signaling pathways. It is also an intrinsically disordered protein and considered "undruggable". In the present study, we confirmed that knocking out SDC4 in pancreatic cancer cells markedly impaired macropinocytosis, colony formation, as well as xenograft tumor initiation and growth. Quantitative proteomic profiling of Sdc4 knockout (KO) cells revealed significant changes in cell metabolic pathways. In a cellular protein-based ligand interaction screening, we identified that Eltrombopag (ETBP), an FDA-approved agonist of the thrombopoietin receptor (TPOR) for immune thrombocytopenia, could directly bind to SDC4 with a Kd value of similar to 2 mu M. We showed that the transmembrane motif was essential for SDC4 binding to ETBP. Unexpectedly, ETBP not only increased SDC4 abundance, but also enhanced SDC4-associated MAPK signaling pathway and macropinocytosis in cancer cells. Our results indicate that ETBP is a potential agonist of SDC4 in a fashion similar to its original target TPOR, and that caution should be taken when using ETBP for chemotherapy-induced thrombocytopenia in cancer patients.
关键词	Syndecan-4 eltrombopag MAPK signaling pathway macropinocytosis cancer
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	Natural Science Foundation of China["31800668","81703757","81874210","81874319"] ; Science and Technology Commission of Shanghai Municipality["18401933500","21S11900900"] ; Shanghai Municipal Education Commission["2019-01-07-00-10-E00072","2021-01-07-0010-E00116"] ; Shanghai Youth Talent Support Program, Shuguang Project[19SG40]
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000820205900017
出版者	E-CENTURY PUBLISHING CORP
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/214806
专题	生命科学与技术学院_公共科研平台_组学分析平台
通讯作者	Ke, Xisong; Zhou, Xianglian; Qu, Yi
作者单位	1.Shanghai Univ Tradit Chinese Med, Ctr Chem Biol, Inst Interdisciplinary Integrat Med Res, Shanghai, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, Inst Interdisciplinary Integrat Med Res, Shanghai, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Cui, Can,Pan, Yuting,Zhang, Chengqian,et al. Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2022,12(6).
APA	Cui, Can.,Pan, Yuting.,Zhang, Chengqian.,Zhu, Darong.,Xuan, Ying.,...&Qu, Yi.(2022).Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells.AMERICAN JOURNAL OF CANCER RESEARCH,12(6).
MLA	Cui, Can,et al."Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells".AMERICAN JOURNAL OF CANCER RESEARCH 12.6(2022).