期刊
MARINE DRUGS
卷 13, 期 10, 页码 6259-6273出版社
MDPI
DOI: 10.3390/md13106259
关键词
gliotoxin; marine secondary metabolites; anti-tumor activity; Wnt signaling pathway; colorectal cancer; proliferation; apoptosis
资金
- Guangdong Provincial Department of Science and Technology [2012B050500004]
- Guangdong Innovative Research Team Program [2009010058]
- National Key Clinical Discipline
- National Natural Science Foundation of China [81301978]
- Science and Information Technology Bureau of Guangzhou, Guangdong [2011J5200009]
- Overseas Excellent Professor Project, Ministry of Education, China
- Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT) for Program of Japan Initiative for Global Research Network on Infectious Diseases (J-GRID)
The discovery of new bioactive compounds from marine natural sources is very important in pharmacological research. Here we developed a Wnt responsive luciferase reporter assay to screen small molecule inhibitors of cancer associated constitutive Wnt signaling pathway. We identified that gliotoxin (GTX) and some of its analogues, the secondary metabolites from marine fungus Neosartorya pseufofischeri, acted as inhibitors of the Wnt signaling pathway. In addition, we found that GTX downregulated the -catenin levels in colorectal cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or activating mutations of -catenin. Furthermore, we demonstrated that GTX induced growth inhibition and apoptosis in multiple colorectal cancer cell lines with mutations of the Wnt signaling pathway. Together, we illustrated a practical approach to identify small-molecule inhibitors of the Wnt signaling pathway and our study indicated that GTX has therapeutic potential for the prevention or treatment of Wnt dependent cancers and other Wnt related diseases.
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