机构：[1]Faculty of Life Science, Kunming University of Science and Technology, Kunming 650500, China[2]Medical School, Kunming University of Science and Technology, Kunming 650500, China[3]The First Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, 650032, China云南省第一人民医院[4]State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China[5]Yunnan Province Clinical Research Center for Hematologic Disease, Kunming 650032, China
The dysregulation of Wnt/13-catenin signaling pathway is closely related to tumorigenesis, metastasis and cancer stem cell maintenance. Salinomycin is a polyether ionophore antibiotic that selectively eliminates cancer stem cells by inhibiting the Wnt/13-catenin signal pathway. Salinomycin selectively target cancer stem cells, but the toxicity limits its further use. In this study, we explore the anti-tumor mechanism of one most active salinomycin C20-O-alkyl oximederivative SAL-98 and found that SAL-98 exerts 10 times higher anti-tumor and anti-CSCs activities compared with salinomycin, which induces cell cycle arrest, ER stress and mitochondria dysfunction and inhibits Wnt/13-catenin signal pathway in vitro with high efficacy. Moreover, SAL-98 shows good antimetastasis effect in vivo. In addition, SAL-98 demonstrates same anti-tumor activities as salinomycin with less 5 times concentration in vivo, the ER stress, autophagy and anti-CSCs effects were also confirmed in vivo. Mechanistically, SAL-98 inhibits the Wnt/13-catenin signaling pathway associated with CHOP expression induced by ER stress, the induced CHOP disrupts the 13-catenin/TCF4 complex and represses the Wnt targeted genes. This study provides an alternative strategy for rational drug development to target Wnt/13-catenin signaling pathway.
基金：
Yunnan (Kunming) Zhou Demin Expert Workstation Project [YSZJGZZ-2020046]; Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project on Applied Basic Research [202201AY070001-238]; Yunnan Provincial Department of Education-Postgraduate Program of Science Research Foundation [241620220085]; Beijing Natural Science Foundation [7234404]
第一作者机构：[1]Faculty of Life Science, Kunming University of Science and Technology, Kunming 650500, China[2]Medical School, Kunming University of Science and Technology, Kunming 650500, China
共同第一作者：
通讯作者：
通讯机构：[2]Medical School, Kunming University of Science and Technology, Kunming 650500, China[4]State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China[5]Yunnan Province Clinical Research Center for Hematologic Disease, Kunming 650032, China[*1]Medical School, Kunming University of Science & Technology, 727 South Jing Ming Road, Chenggong County, Kunming, Yunnan Province 650500, China
推荐引用方式(GB/T 7714)：
Tang Lei,Duan Wenfang,Zhang Chi,et al.Potent salinomycin C20-O-alkyl oxime derivative SAL-98 efficiently inhibits tumor growth and metastasis by affecting Wnt/13-catenin signal pathway[J].BIOCHEMICAL PHARMACOLOGY.2023,214:doi:10.1016/j.bcp.2023.115666.
APA：
Tang, Lei,Duan, Wenfang,Zhang, Chi,Shi, Yulu,Tu, Wenlian...&Zhang, Jihong.(2023).Potent salinomycin C20-O-alkyl oxime derivative SAL-98 efficiently inhibits tumor growth and metastasis by affecting Wnt/13-catenin signal pathway.BIOCHEMICAL PHARMACOLOGY,214,
MLA：
Tang, Lei,et al."Potent salinomycin C20-O-alkyl oxime derivative SAL-98 efficiently inhibits tumor growth and metastasis by affecting Wnt/13-catenin signal pathway".BIOCHEMICAL PHARMACOLOGY 214.(2023)
