Original Article:
The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells
Ziwei Liang, et al.
Cancer Letters,2021, 513, 90-100.
10.1016/j.canlet.2021.05.003
LDN193189 is a highly potent small molecule BMP inhibitor that inhibits BMP type I receptors ALK2 (IC50: 5 nM), ALK3 (IC50: 30 nM) and ALK6 (TGFβ1/BMP signaling) and subsequent SMAD phosphorylation.
Studies have shown that tumor-initiating cells (TICs) are responsible for cancer recurrence and metastasis and are a self-renewing and highly tumorigenic cell subset in several cancers, including hepatocellular carcinoma (HCC). Finding compounds that target phosphorylation of CD133 would provide an effective anti-TIC approach.
In this study, through small molecule chip screening, it was found that the compound LDN193189 binds to the C-terminus of CD133 and inhibits its tyrosine phosphorylation. By downregulating tyrosine phosphorylation of CD133, LDN193189 inhibits self-renewal, immune escape, and tumorigenicity of hepatic TICs. The specific action mechanism of LDN193189 includes: (1) LDN193189 suppresses the phosphorylation of CD133 at Y828 and Y852. (2) LDN193189 reduces the tumorigenesis of liver TICs by downregulating CD133 phosphorylation. (3) LDN193189 suppresses the transcription of Galectin-3 by downregulating CD133 phosphorylation. (4) Galectin-3 suppresses the proliferation of CD8+ T cells by binding to PD-1. In summary, LDN193189 is expected to be a candidate drug for the treatment of HCC.
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