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 ß-catenin nuclear translocation and ß-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 ß-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.
Subject(s)
Forkhead Box Protein M1/metabolism , Lignans/pharmacology , Lysosomes/metabolism , beta Catenin/metabolism , Active Transport, Cell Nucleus/drug effects , Alnus/chemistry , Animals , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cells, Cultured , Forkhead Box Protein M1/genetics , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , HEK293 Cells , Humans , Lignans/chemistry , Mice, Inbred C57BL , Molecular Structure , Proteolysis/drug effects , beta Catenin/geneticsABSTRACT
Pancreatic cancer is one of the leading causes of cancer, and it has the lowest 5-year survival rates. It is necessary to develop more potent anti-pancreatic cancer drugs to overcome the fast metastasis and resistance to surgery, radiotherapy, chemotherapy, and combinations of these. We have identified several diarylheptanoids as anti-pancreatic cancer agents from Alpinia officinarum (lesser galangal) and Alnus japonica. These diarylheptanoids suppressed cell proliferation and induced the cell cycle arrest of pancreatic cancer cells (PANC-1). Among them, the most potent compounds 1 and 7 inhibited the shh-Gli-FoxM1 pathway and their target gene expression in PANC-1 cells. Furthermore, they suppressed the expression of the cell cycle associated genes that were rescued by the overexpression of exogenous FoxM1. Taken together, (E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (1) from Alpinia officinarum (lesser galangal) and platyphyllenone (7) from Alnus japonica inhibit PANC-1 cell proliferation by suppressing the shh-Gli-FoxM1 pathway, and they can be potential candidates for anti-pancreatic cancer drug development.
Subject(s)
Alpinia/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Diarylheptanoids/pharmacology , Forkhead Box Protein M1/antagonists & inhibitors , Hedgehog Proteins/antagonists & inhibitors , Zinc Finger Protein GLI1/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Proliferation/drug effects , Cells, Cultured , Diarylheptanoids/chemistry , Diarylheptanoids/isolation & purification , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Forkhead Box Protein M1/metabolism , HEK293 Cells , Hedgehog Proteins/metabolism , Humans , Molecular Structure , Structure-Activity Relationship , Zinc Finger Protein GLI1/metabolismABSTRACT
Oxidative stress promotes several diseases, including liver disease. We have isolated several stilbenoids from Rheum undulatum to investigate their hepatoprotective activities and mechanism. Stilbenoids from R. undulatum protects hepatocytes against arachidonic acid + iron (AA + Fe) induced oxidative stress. Pterostilbene (compound 5) shows stronger activity than the others. Trimethoxystilbenoid (compound 6) shows best activity on protection of HepG2 cells from AA + Fe-induced oxidative stress, and trans-stilbenoid (compound 7) shows weak activity. These stilbenoids suppress ROS generation in AA + Fe-treated HepG2 cells and also suppress AA + Fe-induced MMP disruption. Their protective effects on AA + Fe-induced MMP disruption were abrogated by treatment of AMP-activated protein kinase (AMPK) inhibitor, compound C or transfection of dominant negative form of AMPK. Taken together, stilbenoids from R. undulatum protect hepatocytes against AA + Fe-induced oxidative stress through AMPK activation. And the methoxy groups in the aryl groups are important for their cytoprotective activity.
