2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/β-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is...

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Bibliographic Details
Published in:	International journal of molecular sciences 2020-08, Vol.21 (16), p.5901
Main Authors:	Chang, Te-Sheng, Lu, Chung-Kuang, Hsieh, Yung-Yu, Wei, Kuo-Liang, Chen, Wei-Ming, Tung, Sui-Yi, Wu, Cheng-Shyong, Chan, Michael W Y, Chiang, Ming-Ko
Format:	Article
Language:	eng
Subjects:	2,4-diamino-quinazoline Aged Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Axin Protein - genetics Axin Protein - metabolism Cell adhesion & migration Cell Line Cell Line, Tumor Cells, Cultured Clinical trials Female Gastric cancer Gene expression Genes Humans Inhibitors Lymphoid Enhancer-Binding Factor 1 - antagonists & inhibitors Lymphoid Enhancer-Binding Factor 1 - genetics Lymphoid Enhancer-Binding Factor 1 - metabolism Male Metastases Mice Mice, Nude Middle Aged Myc protein Neoplasm Metastasis Organoids Patients Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Quinazolines - pharmacology Quinazolines - therapeutic use Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Sequence analysis Signal transduction Signaling Stomach cancer Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Tumorigenesis Tumors Wnt protein Wnt signaling Wnt Signaling Pathway - drug effects Xenografts Xenotransplantation β-Catenin
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Summary:	Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/β-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/β-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.
ISSN:	1422-0067 1661-6596 1422-0067