Abstract
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.
Highlights
The natural flavone apigenin (4′,5,7-trihydroxyflavone) is abundant in fruits and vegetables
Thereafter the Axin complex will be translocated from the cytoplasm to the cell membrane with the help of MACF17 and bind to phosphorylated lipoprotein receptor-related protein 5/6 (LRP5/6) through Axin, and Axin will be degraded. β-catenin will be released, accumulated in the cytoplasm, move into the nucleus, bind to T-cell factor/lymphoid enhancer factor (TCF/LEF), and activate the expression of Wnt-3a-conditioned medium (Wnt) target genes, such as c-Myc, cyclin D1 and Axin[26, 8]
In order to look for potential drugs that inhibit Wnt/β-catenin signaling, we have set up a drug screening platform based on the β-catenin/TCF-mediated transcriptional activity assay[21] and have successfully picked up several candidates that can inhibit Wnt signaling from natural compounds, modified compounds, and Chinese herbs, and one of them is apigenin
Summary
The natural flavone apigenin (4′,5,7-trihydroxyflavone) is abundant in fruits and vegetables. In the condition of without Wnt, members of the Wnt signaling pathway such as Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), microtubule actin crosslinking factor 1 (MACF1)[7] and beta-catenin (CTNNB1) form a protein complex termed the “β-catenin destruction complex” or “Axin complex” in the cytoplasm. In this complex, β-catenin will be phosphorylated by GSK3β and CK1α on serines 33, 37, 45 and threonine 41 and subsequently be tagged with polyubiquitin before its destruction by the 26S proteasome degradation system. At the end of autophagy, cargos, LC3 and SQSTM1/p62 will eventually be degraded in the autolysosome
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