The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells
The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells
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LDN193189与CD133 C端的结合抑制肝脏肿瘤起始细胞的肿瘤发生和免疫逃逸
DOI：
10.1016/j.canlet.2021.05.003
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发表时间：
2021
期刊：
影响因子：
9.7
通讯作者：
Jiang Jianhai
中科院分区：
文献类型：
--
作者：
Liang Ziwei;Wu Bingrui;Ji Zhi;Liu Weitao;Shi Danfang;Chen Xiaoning;Wei Yuanyan;Jiang Jianhai
肿瘤起始细胞（TIC）标志物CD 133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，发现靶向CD 133磷酸化的化合物将提供抑制TIC特性的有效方法。在此，通过小分子微阵列筛选，发现化合物LDN 193189与CD 133的c-末端结合并影响其酪氨酸磷酸化。LDN 193189抑制CD 133和p85之间的相互作用，同时降低肝脏TIC的自我更新和致瘤性。此外，LDN 193189通过降低CD 133的酪氨酸磷酸化来抑制Galectin-3的表达和转录。由肝TIC分泌的半乳糖凝集素-3通过与PD-1结合来抑制活化的CD 8 +T细胞的增殖。LDN 193189通过下调Galectin-3抑制肝脏TIC的免疫逃逸能力。总之，LDN 193189通过靶向CD 133-Galectin-3轴抑制肝CSC的肿瘤发生和免疫逃逸。
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.