Expression of E-cadherin reduces Bcl-2 expression and increases sensitivity to etoposide-induced apoptosis

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Abstract

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 β-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 β-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 β-catenin. Loss of E-cadherin in invasive tumor cells may lead to increased Bcl-2 expression and resistance to chemotherapeutic drugs.

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Sasaki, C. Y., Lin, H. C., & Passaniti, A. (2000). Expression of E-cadherin reduces Bcl-2 expression and increases sensitivity to etoposide-induced apoptosis. International Journal of Cancer, 86(5), 660–666. https://doi.org/10.1002/(SICI)1097-0215(20000601)86:5<660::AID-IJC9>3.0.CO;2-X

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