LDN193189与CD133 C末端的结合可抑制肝肿瘤起始细胞的肿瘤发生和免疫逃逸。

The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells.

作者信息

Liang Ziwei, Wu Bingrui, Ji Zhi, Liu Weitao, Shi Danfang, Chen Xiaoning, Wei Yuanyan, Jiang Jianhai

机构信息

NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China.

出版信息

Cancer Lett. 2021 Aug 10;513:90-100. doi: 10.1016/j.canlet.2021.05.003. Epub 2021 May 10.

DOI:10.1016/j.canlet.2021.05.003

PMID:33984420

Abstract

The tumor-initiating cell (TIC) marker CD133 promotes TIC self-renewal and tumorigenesis through the tyrosine phosphorylation of its c-terminal domain. Therefore, finding compounds that target the phosphorylation of CD133 will provide an effective method for inhibiting TICs characteristics. Here, through small molecule microarray screening, compound LDN193189 was found to bind to the c-terminus of CD133 and influenced its tyrosine phosphorylation. LDN193189 inhibited the interaction between CD133 and p85, accompanied by a reduction in the self-renewal and tumorigenicity of liver TIC. In addition, LDN193189 inhibited the expression and transcription of Galectin-3 by reducing the tyrosine phosphorylation of CD133. Galectin-3 secreted by liver TICs inhibited the proliferation of activated CD8 T cells by binding to PD-1. LDN193189 suppressed the immune escape ability of liver TICs by downregulating Galectin-3. Taken together, LDN193189 suppressed the tumorigenesis and immune escape of liver CSCs by targeting the CD133-Galectin-3 axis.

摘要

肿瘤起始细胞（TIC）标志物CD133通过其C末端结构域的酪氨酸磷酸化促进TIC自我更新和肿瘤发生。因此，寻找靶向CD133磷酸化的化合物将为抑制TIC特性提供一种有效方法。在此，通过小分子微阵列筛选，发现化合物LDN193189与CD133的C末端结合并影响其酪氨酸磷酸化。LDN193189抑制CD133与p85之间的相互作用，同时肝TIC的自我更新和致瘤性降低。此外，LDN193189通过降低CD133的酪氨酸磷酸化来抑制半乳糖凝集素-3的表达和转录。肝TIC分泌的半乳糖凝集素-3通过与PD-1结合抑制活化的CD8 T细胞增殖。LDN193189通过下调半乳糖凝集素-3抑制肝TIC的免疫逃逸能力。综上所述，LDN193189通过靶向CD133-半乳糖凝集素-3轴抑制肝CSC的肿瘤发生和免疫逃逸。