ToxSci Advance Access first published online on September 12, 2008
This version published online on September 16, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn197
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Presenilin 1/
-secretase is associated with cadmium-induced E-cadherin cleavage and COX-2 gene expression in T47D breast cancer cells
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* Division of Brain Diseases, Center for Biomedical Sciences, National Institute of Health, 194, Tongillo, Eunpyeong-gu, Seoul, 122-701, Korea
Department of Molecular Medicine, Ewha Womans University Medical College, 911-1 Mok-6-dong, Yangchon-gu, Seoul 158-710, South Korea
Department of Herbal Pharmaceutical Development, Korea Institute of Oriental Medicine, 461-24 Jeonmin-dong, Yuseng-gu, Daejeon 305-811, Republic of Korea
¶ To whom correspondence should be addressed. Fax: + 82 2 354 1057. E-mail address: kohyoungho122{at}gmail.com (YH Koh).
Received July 1, 2008; revision received September 10, 2008; accepted September 10, 2008
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Abstract |
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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 role(s) of E-cadherin and cadmium in and the mechanism(s) of tumor progression remain to be defined. Here, we demonstrate that cadmium increases E-cadherin processing via a 
-secretase in the T47D breast cancer cell lines. This presenilin 1/-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, -secretase inhibitors (DAPT and L-685,486), anti-oxidants (NAC and MnTmPyP) or a calcium-chelating drug (BAPTA-AM). 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, 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 -secretase, which increases cell motility and invasion ability. Understanding the downstream signaling cascade(s) of cadmium that promote(s) tumor progression might be a key to the development of novel therapeutic strategies.
Key Words: cadmium; -secretase; COX-2; E-cadherin; apoptosis.
These authors contributed equally to this work.