title: E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2.
abstract: The role of E-cadherin in tumorigenesis has been attributed to its ability to suppress invasion and metastization. However, E-cadherin impairment may have a wider impact on tumour development. We have previously shown that overexpression of mutant human E-cadherin in Drosophila produces a phenotype characteristic of downregulated Notch. Hence, we hypothesized that Notch signalling may be influenced by E-cadherin and may mediate tumour development associated with E-cadherin deficiency. De novo expression of wild-type E-cadherin in two cellular models led to a significant decrease in the activity of the Notch pathway. In contrast, the ability to inhibit Notch-1 signalling was lost in cells transfected with mutant forms of E-cadherin. Increased Notch-1 activity in E-cadherin-deficient cells correlated with increased expression of Bcl-2, and increased resistance to apoptotic stimuli. After Notch-1 inhibition, E-cadherin-deficient cells were re-sensitized to apoptosis in a similar degree to wild-type E-cadherin cells. We also show that Notch-inhibiting drugs are able to significantly inhibit the growth of E-cadherin-deficient cells xenografted into nude mice. This effect was comparable with the one observed in animals treated with the chemotherapeutic agent taxol, a chemical inducer of cell death. In conclusion, our results show that aberrant Notch-1 activation, Bcl-2 overexpression and increased cell survival are likely to play a crucial role in neoplastic transformation associated with E-cadherin impairment. These findings highlight the possibility of new targeted therapeutical strategies for the treatment of tumours associated with E-cadherin inactivation.
authors: IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
authors: António Carlos
authors: AC
authors: Ferreira
authors: Gianpaolo
authors: G
authors: Suriano
authors: Nuno
authors: N
authors: Mendes
authors: Bárbara
authors: B
authors: Gomes
authors: Xiaogang
authors: X
authors: Wen
authors: Fátima
authors: F
authors: Carneiro
authors: Raquel
authors: R
authors: Seruca
authors: José Carlos
authors: JC
authors: Machado
mesh_terms: D015820:Cadherins / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D015820:Cadherins; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch