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

Title
Presenilin 1/γ-secretase is associated with cadmium-induced e-cadherin cleavage and COX-2 gene expression in T47D breast cancer cells
Authors
Park C.S.Kim O.S.Yun S.-M.Jo S.A.Jo I.Koh Y.H.
Ewha Authors
조인호
SCOPUS Author ID
조인호scopus
Issue Date
2008
Journal Title
Toxicological Sciences
ISSN
1096-6080JCR Link
Citation
vol. 106, no. 2, pp. 413 - 422
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
DOI
10.1093/toxsci/kfn197
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의과대학 > 의학과 > Journal papers
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