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

Wan Mohaiza Dashwood, Orianna Carter, Mohamed Al-Fageeh, Qingjie Li, Roderick H. Dashwood

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

β-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 β-catenin, since this provides an avenue for the prevention of colorectal and other cancers in which β-catenin is frequently over-expressed. We show here that physiologically relevant concentrations of the tea polyphenol epigallocatechin-3-gallate (EGCG) inhibited β-catenin/TCF- dependent reporter activity in human embryonic kidney 293 cells transfected with wild type or mutant β-catenins, and there was a corresponding decrease in β-catenin protein levels in the nuclear, cytosolic and membrane-associated fractions. However, β-catenin accumulated as punctate aggregates in response to EGCG treatment, including in human colon cancer cells over-expressing β-catenin endogenously. Confocal microscopy studies revealed that the aggregated β-catenin in HEK293 cells was extra-nuclear and co-localized with lysosomes, suggesting that EGCG activated a pathway involving lysosomal trafficking of β-catenin. Lysosomal inhibitors leupeptin and transepoxysuccinyl-l-leucylamido(4-guanido)butane produced an increase in β-catenin protein in total cell lysates, without a concomitant increase in β-catenin transcriptional activity. These data provide the first evidence that EGCG facilitates the trafficking of β-catenin into lysosomes, presumably as a mechanism for sequestering β-catenin and circumventing further nuclear transport and activation of β-catenin/TCF/LEF signaling.

Original languageEnglish (US)
Pages (from-to)161-172
Number of pages12
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume591
Issue number1-2
DOIs
StatePublished - Dec 11 2005
Externally publishedYes

Fingerprint

Catenins
Polyphenols
Tea
TCF Transcription Factors
epigallocatechin gallate
Lysosomes
Cell Nucleus Active Transport
HEK293 Cells
Nuclear Envelope
Cadherins
Human Activities
Cell Adhesion
Confocal Microscopy

Keywords

  • β-Catenin/TCF/LEF signaling
  • Colon cancer
  • EGCG
  • Lysosomes
  • Proteasomes

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Lysosomal trafficking of β-catenin induced by the tea polyphenol epigallocatechin-3-gallate. / Dashwood, Wan Mohaiza; Carter, Orianna; Al-Fageeh, Mohamed; Li, Qingjie; Dashwood, Roderick H.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 591, No. 1-2, 11.12.2005, p. 161-172.

Research output: Contribution to journalArticle

Dashwood, Wan Mohaiza ; Carter, Orianna ; Al-Fageeh, Mohamed ; Li, Qingjie ; Dashwood, Roderick H. / Lysosomal trafficking of β-catenin induced by the tea polyphenol epigallocatechin-3-gallate. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2005 ; Vol. 591, No. 1-2. pp. 161-172.
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