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: Guang-Zhi Dong, Ji Hye Jeong, Yu-Ih Lee, Yeong Eun Han, Jung Sook Shin, Yoon-Jung Kim, Raok Jeon, Young Hwa Kim, Tae Jun Park, Keun Il Kim, Jae-Ha Ryu
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 45951 (04 05 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28378765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Lignans
• beta Catenin

Topics

• Active Transport, Cell Nucleus (drug effects)
• Alnus (chemistry)
• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cells, Cultured
• Forkhead Box Protein M1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HEK293 Cells
• Humans
• Lignans (chemistry, pharmacology)
• Lysosomes (metabolism)
• Mice, Inbred C57BL
• Molecular Structure
• Proteolysis (drug effects)
• beta Catenin (genetics, metabolism)