期刊
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
卷 591, 期 1-2, 页码 161-172出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2005.03.029
关键词
beta-catenin/TCF/LEF signaling; EGCG; colon cancer; proteasomes; lysosomes
资金
- NCI NIH HHS [R01 CA065525-08, P01 CA090890-05S1, R01 CA065525-09, P01 CA090890-01A29001, CA65525, P01 CA090890-01A20003, P01 CA090890, CA90890, R01 CA080176, R01 CA080176-04, R01 CA080176-05, CA80176, R01 CA065525, R29 CA065525, P01 CA090890-05] Funding Source: Medline
- NIEHS NIH HHS [P30 ES000210, T32 ES007060, P30 ES00210, T32 ES07060] Funding Source: Medline
beta-Catenin is a cadherin-binding protein involved in cell-cell adhesion, which also functions as a transcriptional activator when complexed in the nucleus with members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of proteins. There is considerable interest in mechanisms that down-regulate beta-catenin, since this provides an avenue for the prevention of colorectal and other cancers in which beta-catenin is frequently over-expressed. We show here that physiologically relevant concentrations of the tea polyphenol epigallocatechin-3-gallate (EGCG) inhibited beta-catenin/TCF-dependent reporter activity in human embryonic kidney 293 cells transfected with wild type or mutant beta-catenins, and there was a corresponding decrease in beta-catenin protein levels in the nuclear, cytosolic and membrane-associated fractions. However, beta-catenin accumulated as punctate aggregates in response to EGCG treatment, including in human colon cancer cells over-expressing beta-catenin endogenously. Confocal microscopy studies revealed that the aggregated beta-catenin in HEK293 cells was extra-nuclear and co-localized with lysosomes, suggesting that EGCG activated a pathway involving lysosomal trafficking of beta-catenin. Lysosomal inhibitors leupeptin and transepoxysuccinyl-L-leucylamido(4-guanido)butane produced an increase in beta-catenin protein in total cell lysates, without a concomitant increase in beta-catenin transcriptional activity. These data provide the first evidence that EGCG facilitates the trafficking of beta-catenin into lysosomes, presumably as a mechanism for sequestering beta-catenin and circumventing further nuclear transport and activation of beta-catenin/TCF/LEF signaling. (c) 2005 Elsevier B.V. All rights reserved.
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