Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling.
The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/β-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear β-catenin, leading to the suppression in the β-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of β-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of β-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player β-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.
Department of Biotechnology, Ming-Chuan University, Taoyuan, 33348, Taiwan.
Chung-Ming
CM
Lin
Division of Plastic and Reconstructive Surgery, Department of Surgery, China Medical University Hospital, Taichung, 40402, Taiwan.
Hsin-Han
HH
Chen
Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402, Taiwan.
Chun-An
CA
Lin
Department of Biotechnology, Ming-Chuan University, Taoyuan, 33348, Taiwan.
Hui-Chung
HC
Wu
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
Jim Jinn-Chyuan
JJ
Sheu
Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402, Taiwan. huijyechen@mail.cmu.edu.tw.|Department of Nursing, Asia University, Taichung, 40354, Taiwan. huijyechen@mail.cmu.edu.tw.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan. huijyechen@mail.cmu.edu.tw.
Hui-Jye
HJ
Chen
D047310:Apigenin / Q000008:administration & dosage*; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism; D000072261:Dishevelled Proteins / Q000378:metabolism; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; D000072261:Dishevelled Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051176:beta Catenin; D047310:Apigenin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases