Presenilin 1/gamma-secretase is associated with cadmium-induced E-cadherin cleavage and COX-2 gene expression in T47D breast cancer cells.
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 gamma-secretase in the T47D breast cancer cell lines. This presenilin 1 (PS1)/gamma-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, gamma-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 gamma-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.
Park
Chang Seok
CS
Division of Brain Diseases, Center for Biomedical Sciences, National Institute of Health, 194, Tongillo, Eunpyeong-gu, Seoul, 122-701, Korea.
Kim
Ohn Soon
OS
Yun
Sang-Moon
SM
Jo
Sangmee A
SA
Jo
Inho
I
Koh
Young Ho
YH
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002104:Cadmium / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D053764:Presenilin-1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015820:Cadherins; D017931:DNA Primers; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D002104:Cadmium; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium