Snail blocks the cell cycle and confers resistance to cell death

Abstract

The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the expression of mesenchymal markers. Here, we show that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals. Hence, Snail favors changes in cell shape versus cell division, indicating that with respect to oncogenesis, although a deregulation/increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization. Finally, the resistance to cell death conferred by Snail provides a selective advantage to embryonic cells to migrate and colonize distant territories, and to malignant cells to separate from the primary tumor, invade, and form metastasis.

Akt2 interacts with Snail1 in the E-cadherin promoter

“…P Villagrasa et al activated by expression of this EMT inductor (this report; see also Vega et al, 2004;Escriva`et al, 2008). Activation of Akt has been related to another very relevant consequence of Snail1 expression in cell lines: acquisition of resistance to apoptotic insults (Vega et al, 2004).…”

“…Activation of Akt has been related to another very relevant consequence of Snail1 expression in cell lines: acquisition of resistance to apoptotic insults (Vega et al, 2004). In this article, we have analyzed Akt activation by not only determining the phosphorylation of key residues in the Akt molecule, but also by directly measuring its kinase activity on Crosstide, a small peptide widely used as an Akt substrate (Alessi et al, 1996).…”

“…P Villagrasa et al upregulated Snail1 expression detected in many cells in response to apoptotic insults, as Snail1 protects epithelial cells from cell death (Vega et al, 2004;Escriva`et al, 2008). More studies will be required to determine the specific role of this histone modification in gene expression.…”

“…Besides these effects on Snail1 expression, Akt has also been positioned downstream from Snail1 in transforming growth factorb-induced EMT (Cho et al, 2007). Snail1 overexpression stimulates this protein kinase as it increased the levels of phosphoThr308 (P-Thr308) in Akt, at least in part through direct repression of PTEN, an inhibitor of Akt activation (Vega et al, 2004;Escriva`et al, 2008). This upregulated Akt activity is probably the cause of the apoptosis resistance induced by Snail1 in several cell lines (Vega et al, 2004).…”

Snail silencing effectively suppresses tumour growth and invasiveness

“…More importantly, Snail is expressed at the invasive front of epidermoid carcinomas (Cano et al, 2000) and has been associated to the lymph node status and/or invasiveness of ductal breast carcinomas and hepatocarcinomas (Blanco et al, 2002;Sugimachi et al, 2003) and to local recurrence of breast tumours (Moody et al, 2005). In addition, Snail expression has been shown to confer resistance to cell death mediated by several factors and chemotherapeutic agents (Kajita et al, 2004;Vega et al, 2004). These evidences support a key role for Snail as inducer of tumour invasion as well as potentially contributing to tumour growth and/or chemoresistance mechanisms, therefore, providing a new therapeutic target.…”