Expression of E-cadherin reduces bcl-2 expression and increases sensitivity to etoposide-induced apoptosis.
Expression of Bcl-2 is important in determining cancer cell resistance to chemotherapy. However, it is not clear whether cell-cell interactions regulate Bcl-2 expression. Using rat breast carcinoma cells selected for loss of hormone responsiveness, we found that parental E-cadherin-expressing cells (E cells) were more sensitive to etoposide-induced apoptosis than hormone-non-responsive cells (F cells), which failed to express E-cadherin. Expression of beta-catenin and pp120 src substrate proteins, which associate with E-cadherin, was unaffected. To determine whether re-expression of E-cadherin in F cells would restore etoposide sensitivity, F cells were transfected with an expression vector coding for the mouse E-cadherin gene. Stable clonal isolates expressing E-cadherin (F. Cad) showed increased sensitivity to etoposide treatment compared with control clones (F.Neo). Expression of E-cadherin resulted in a redistribution of beta-catenin from the cytoskeletal/nuclear fraction to the cytoplasmic/membrane fraction of the cells. E-cadherin-expressing clones also showed reduced invasion through basement membrane. Etoposide-induced apoptosis was characterized by morphological changes (nuclear blebbing) and DNA fragmentation. Induction of CPP32-like caspase activity was also observed in F.Cad transfectants but not F.Neo cells. Unlike F cells, F.Cad transfectants were not able to express Bcl-2, but transient transfection of bcl-2 resulted in re-expression and resistance to etoposide treatment. Therefore, E-cadherin may negatively regulate Bcl-2 expression by altering the availability of nuclear beta-catenin. Loss of E-cadherin in invasive tumor cells may lead to increased Bcl-2 expression and resistance to chemotherapeutic drugs.
Sasaki
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CY
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Lin
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Hc
Passaniti
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A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology*; D015870:Gene Expression; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide