E-cadherin is required for caveolin-1-mediated down-regulation of the inhibitor of apoptosis protein survivin via reduced beta-catenin-Tcf/Lef-dependent transcription.
Caveolin-1 reportedly acts as a tumor suppressor and promotes events associated with tumor progression, including metastasis. The molecular mechanisms underlying such radical differences in function are not understood. Recently, we showed that caveolin-1 inhibits expression of the inhibitor of apoptosis protein survivin via a transcriptional mechanism involving the beta-catenin-Tcf/Lef pathway. Surprisingly, while caveolin-1 expression decreased survivin mRNA and protein levels in HT29(ATCC) human colon cancer cells, this was not the case in metastatic HT29(US) cells. Survivin down-regulation was paralleled by coimmunoprecipitation and colocalization of caveolin-1 with beta-catenin in HT29(ATCC) but not HT29(US) cells. Unlike HT29(ATCC) cells, HT29(US) cells expressed small amounts of E-cadherin that accumulated in intracellular patches rather than at the cell surface. Re-expression of E-cadherin in HT29(US) cells restored the ability of caveolin-1 to down-regulate beta-catenin-Tcf/Lef-dependent transcription and survivin expression, as seen in HT29(ATCC) cells. In addition, coimmunoprecipitation and colocalization between caveolin-1 and beta-catenin increased upon E-cadherin expression in HT29(US) cells. In human embryonic kidney HEK293T and HT29(US) cells, caveolin-1 and E-cadherin cooperated in suppressing beta-catenin-Tcf/Lef-dependent transcription as well as survivin expression. Finally, mouse melanoma B16-F10 cells, another metastatic cell model with low endogenous caveolin-1 and E-cadherin levels, were characterized. In these cells, caveolin-1-mediated down-regulation of survivin in the presence of E-cadherin coincided with increased apoptosis. Thus, the absence of E-cadherin severely compromises the ability of caveolin-1 to develop activities potentially relevant to its role as a tumor suppressor.
Torres
Vicente A
VA
FONDAP Center for Molecular Studies of the Cell, Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago, Chile.
Tapia
Julio C
JC
Rodriguez
Diego A
DA
Lladser
Alvaro
A
Arredondo
Cristian
C
Leyton
Lisette
L
Quest
Andrew F G
AF
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002999:Clone Cells; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000077022:Survivin; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*