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.

Lignan from Alnus japonica Inhibits Adipocyte Differentiation via Cell Cycle and FOXO1 Regulation

“…We isolated the lignan (−)-(2 R ,3 R )-1,4- O -diferuloylsecoisolariciresinol (DFS) from a methanol extract of the Alnus japonica (AJ) stem; its structure was identified by spectroscopic analysis as previously reported ( Figure 1 A) [ 14 ]. To investigate the antiobesity effect of DFS, mouse preadipocyte 3T3-L1 cells were treated with DFS during adipocyte differentiation.…”

“…The chloroform-soluble fraction (28 g) was subjected to silica gel column chromatography, followed by reverse phase chromatography to isolate DFS. The purity of DFS was confirmed by high performance liquid chromatography and observation of the 1 H-nuclear magnetic resonance spectrum [ 14 ].…”

“…We previously isolated (−)-(2 R ,3 R )-1,4- O -diferuloylsecoisolariciresinol (DFS) from an AJ stem that showed anticancer activity in a mouse xenograft model of colon cancer. DFS suppressed cancer cell proliferation through downregulating the FoxM1-Wnt/β-catenin pathway [ 14 ]. Herein, we report the antiobesity effect of DFS and its regulatory mechanism in an adipocyte culture system.…”

MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition

“…FOXM1 is one of the YAP target genes [37], and is a driver of cell proliferation, chemo resistance and cancer progression [28]. FOXM1 has also been shown to promote nuclear localization of β-catenin and induction of canonical WNT target gene transcription during glioma tumorigenesis [41,42]. Based on these observations, and the above mentioned RNAseq results, we explored whether regulation of YAP/FOXM1 signaling were responsible for the MEKi induced elevation in canonical WNT signaling in HCT-15 cells.…”

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

“…Furthermore, FOXM1 has also been shown to regulate the expression of the pluripotency genes sex determining region Y box 2 (Sox2) and Bmi1 to promote stem cell-like properties [111], [112]. FOXM1 can also indirectly influence stem cell maintenance by interacting with β-catenin and inducing its nuclear translocation and transcription activation [113], [114]. The nuclear relocated β-catenin then complexes with T-cell factor/lymphoid enhancer factor (TCF/LEF) to trigger the transcription of Wnt targets which are required for the promotion of stem cell phenotypes in cancer cells [113], [114], [115].…”