Lysosomal trafficking of beta-catenin induced by the tea polyphenol epigallocatechin-3-gallate.

Abstract

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.

• Authors: Wan-Mohaiza Dashwood, Orianna Carter, Mohamed Al-Fageeh, Qingjie Li, Roderick H Dashwood
• Journal: Mutation research (Mutat Res) Vol. 591 Issue 1-2 Pg. 161-72 (Dec 11 2005) ISSN: 0027-5107 [Print] Netherlands
• PMID: 16054165 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticarcinogenic Agents
• Cadherins
• Recombinant Fusion Proteins
• TCF Transcription Factors
• TCF7L2 protein, human
• Tea
• Transcription Factor 7-Like 2 Protein
• beta Catenin
• Catechin
• epigallocatechin gallate

Topics

• Anticarcinogenic Agents (chemistry, metabolism)
• Cadherins (metabolism)
• Catechin (analogs & derivatives, chemistry, metabolism)
• Cell Line
• Colonic Neoplasms (metabolism)
• Colorectal Neoplasms (metabolism)
• Genes, Reporter
• Humans
• Lysosomes (metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Signal Transduction (physiology)
• TCF Transcription Factors (genetics, metabolism)
• Tea (chemistry)
• Transcription Factor 7-Like 2 Protein
• beta Catenin (genetics, metabolism)