title: Gliotoxin Inhibits Proliferation and Induces Apoptosis in Colorectal Cancer Cells.
abstract: 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 β-catenin levels in colorectal cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or activating mutations of β-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.
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. junxiong_ch@sina.com.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. junxiong_ch@sina.com.
authors.forename: Junxiong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. chenliangwang1984@gmail.com.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. chenliangwang1984@gmail.com.|Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China. chenliangwang1984@gmail.com.
authors.forename: Chenliang
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. lanwj@mail.sysu.edu.cn.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Lan
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. huangchunyingdg@163.com.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. huangchunyingdg@163.com.
authors.forename: Chunying
authors.initials: C
authors.lastname: Huang
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. lmmhello@163.com.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. lmmhello@163.com.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Lin
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. seyyawang@163.com.
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. lanwj@mail.sysu.edu.cn.
authors.forename: Wanling
authors.initials: W
authors.lastname: Liang
authors.affiliation: Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. aikichi@zj9.so-net.ne.jp.
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. yangxl28@mail.sysu.edu.cn.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. yangxl28@mail.sysu.edu.cn.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. liuhuanl@mail.sysu.edu.cn.|Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. liuhuanl@mail.sysu.edu.cn.|Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China. liuhuanl@mail.sysu.edu.cn.
authors.forename: Huanliang
authors.initials: H
authors.lastname: Liu
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D005912:Gliotoxin / Q000302:isolation & purification / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D055326:Neosartorya / Q000378:metabolism*; D064210:Secondary Metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics
chemical_list: D051176:beta Catenin; D005912:Gliotoxin; D008156:Luciferases
keywords: Wnt signaling pathway; anti-tumor activity; apoptosis; colorectal cancer; gliotoxin; marine secondary metabolites; proliferation