title: A lignan induces lysosomal dependent degradation of FoxM1 protein to suppress β-catenin nuclear translocation.
abstract: Colon cancer is one of the most common cancers. In this study, we isolated a lignan [(-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica (Betulaceae) and investigated its biological activity and mechanism of action on colon cancer. DFS reduced the viability of colon cancer cells and induced cell cycle arrest. DFS also suppressed β-catenin nuclear translocation and β-catenin target gene expression through a reduction in FoxM1 protein. To assess the mechanism of the action of DFS, we investigated the effect of DFS on endogenous and exogenous FoxM1 protein degradation in colon cancer cells. DFS-induced FoxM1 protein degradation was suppressed by lysosomal inhibitors, chloroquine and bafilomycin A1, but not by knock-down of proteasomal proteins. The mechanism of DFS for FoxM1 degradation is lysosomal dependent, which was not reported before. Furthermore, we found that FoxM1 degradation was partially lysosomal-dependent under normal conditions. These observations indicate that DFS from A. japonica suppresses colon cancer cell proliferation by reducing β-catenin nuclear translocation. DFS induces lysosomal-dependent FoxM1 protein degradation. This is the first report on the lysosomal degradation of FoxM1 by a small molecule. DFS may be useful in treating cancers that feature the elevated expression of FoxM1.
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Guang-Zhi
authors.initials: GZ
authors.lastname: Dong
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Yu-Ih
authors.initials: YI
authors.lastname: Lee
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Yeong Eun
authors.initials: YE
authors.lastname: Han
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Jung Sook
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Yoon-Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Ajou University, Suwon, 16499, Korea.
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Ajou University, Suwon, 16499, Korea.
authors.forename: Tae Jun
authors.initials: TJ
authors.lastname: Park
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.affiliation: Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D029661:Alnus / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D059748:Proteolysis / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D017705:Lignans; D051176:beta Catenin