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

Expression of Ed-a is important in determining cancer cell resistance to ch emotherapy. However, it is not clear whether cell-cell interactions regulat e Bcl-2 expression. Using rat breast carcinoma cells selected for loss of h ormone responsiveness, we found that parental E-cadherin-expressing cells ( E cells) were more sensitive to etoposide-induced apoptosis than hormone-no n-responsive cells (F cells), which failed to express E-cadherin. Expressio n of beta-catenin and ppl20 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 wi th an expression vector coding for the mouse E-cadherin gene. Stable clonal isolates expressing E-cadherin (F,Cad) showed increased sensitivity to eto poside treatment compared with control clones (F,Neo). Expression of E-cadh erin resulted in a redistribution of beta-catenin from the cytoskeletal/nuc lear fraction Co the cytoplasmid/membrane fraction of the cells. E-cadherin -expressing clones also showed reduced invasion through basement membrane. Etoposide-induced apoptosis was characterized by morphological changes (nuc lear blebbing) and DNA fragmentation. Induction of CPP32-like caspase activ ity 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 tr ansfection of bcl-2 resulted in re-expression and resistance to etoposide t reatment, Therefore, E-cadherin may negatively regulate Bcl-2 expression by altering the availability of nuclear beta-catenin, Loss of E-cadherin in i nvasive tumor cells may lead to increased Bcl-2 expression and resistance t o chemotherapeutic drugs. Published 2000 Wiley-Liss, Inc.dagger