Presenilin 1/γ-secretase is associated with cadmium-induced e-cadherin cleavage and COX-2 gene expression in T47D breast cancer cells

Chang Seok Park, Ohn Soon Kim, Sang Moon Yun, Sangmee A. Jo, Inho Jo, Young Ho Koh

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Cadmium is a heavy metal that has multiple toxic effects on human health and has been classified as a human carcinogen. E-cadherin is a major target of cadmium; however, the roles of E-cadherin and cadmium and the mechanisms of tumor progression remain to be defined. Here, we demonstrate that cadmium increases E-cadherin processing via a γ-secretase in the T47D breast cancer cell lines. This presenilin 1 (PS1)/γ-secretase-dependent cleavage of E-cadherin was accompanied by changes in reactive oxygen species or calcium. E-cadherin cleavage was blocked by a PS1 dominant-negative mutant, γ-secretase inhibitors [N-[N-(3,5-Difluorophenacetyl-L-alanyl)]- S-phenylglycine t-butyl ester (DAPT) and L-685,486], antioxidants (N-acetylcysteine and Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), or a calcium chelating drug 1,2-bis(o-Aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester. Immunofluorescence analysis confirmed the disappearance of E-cadherin staining at the cell surface. Those inhibitors attenuated cadmium-induced cytotoxicity. Additionally, cadmium treatment increased cell motility and invasion ability, which was abated by DAPT. Interestingly, cyclooxygenase-2 (COX-2) expression induced by cadmium was also inhibited by DAPT. The cadmium-induced cell motility and invasion ability were inhibited by a COX-2 inhibitor, NS398. Our data indicate a novel molecular mechanism that links cytotoxicity of cadmium and disrupted E-cadherin processing to adherens junctions; cadmium induces COX-2 expression via γ-secretase, which increases cell motility and invasion ability. Understanding the downstream signaling cascades of cadmium that promote tumor progression might be a key to the development of novel therapeutic strategies.

Original languageEnglish
Pages (from-to)413-422
Number of pages10
JournalToxicological Sciences
Volume106
Issue number2
DOIs
StatePublished - 2008

Bibliographical note

Funding Information:
Ministry of Health and Welfare, Korea, and a Korea National Institute of Health Intramural Research Grant (091-4845-300-210-13 to Y.H.K.).

Keywords

  • Apoptosis
  • COX-2
  • Cadmium
  • E-cadherin
  • γ-secretase

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