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Expression of E‐cadherin reduces Bcl‐2 expression and increases sensitivity to etoposide‐induced apoptosis
Author(s) -
Sasaki Carl Y.,
Lin Hshingchi,
Passaniti Antonino
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000601)86:5<660::aid-ijc9>3.0.co;2-x
Subject(s) - cadherin , transfection , biology , etoposide , apoptosis , microbiology and biotechnology , cell culture , catenin , cancer research , cancer cell , cell , signal transduction , cancer , genetics , wnt signaling pathway , chemotherapy
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. Int. J. Cancer 86:660–666, 2000. Published 2000 Wiley‐Liss, Inc.