Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function

Abstract

Differentially from other kinds of Ras, oncogenic K-Ras, which is mutated approximately 30% of human cancer, does not induce apoptosis and senescence. Here, we provide the evidence that oncogenic K-Ras abrogates p53 function and expression through induction of Ataxia telangiectasia-mutated and Rad3-related mediated Snail stabilization. Snail directly binds to DNA binding domain of p53 and diminishes the tumor-suppressive function of p53. Thus, elimination of Snail through si-RNA can induce p53 in K-Ras-mutated cells, whereas Snail and mutant K-Ras can suppress p53 in regardless of K-Ras status. Chemicals, isolated from inhibitor screening of p53-Snail binding, can block the Snail-mediated p53 suppression and enhance the expression of p53 as well as the transcriptional activity of p53 in an oncogenic K-Ras-dependent manner. Among the chemicals, two are very similar in structure. These results can answer why K-Ras can coexist with wild type p53 and propose the Snail-p53 binding as the new therapeutic target for K-Ras-mutated cancers including pancreatic, lung, and colon cancers.

p53, secreted by K-Ras–Snail pathway, is endocytosed by K-Ras-mutated cells; implication of target-specific drug delivery and early diagnostic marker

“…Direct interaction of Snail and p53 reduces the expression of both proteins, whereas the inhibitor of their binding can induce p53 expression in K-Ras-mutated cells (Lee et al, 2009). We have also found that elimination of Snail can induce p53 in K-Ras-mutated cancer cells, but not in wild-type cancer cells.…”

“…p53 was induced more dominantly by si-Snal than by si-MDM2 in K-Rasmutated cell lines (Figure 1c; Bres et al, 2003), suggesting that Snail-mediated p53 suppression is not linked to MDM2-mediated p53 degradation. Indeed, we have already shown that Snail has not altered the p53 half-life, transcript or ubiquitin conjugation (Supplementary Figure S1a; Lee et al, 2009). To confirm this, we measured the p53 expression in Snail-transfected cells after treatment with ALLN/MG132.…”

“…In our earlier result, we have also shown that oncogenic K-Ras suppresses p53 through induction of Snail (Halaschek-Weiner et al, 2004;Kajita et al, 2004;Lee et al, 2009). Direct interaction of Snail and p53 reduces the expression of both proteins, whereas the inhibitor of their binding can induce p53 expression in K-Ras-mutated cells (Lee et al, 2009).…”

“…In mouse models, it has been proven that oncogenic K-Ras-induced tumor cells harbor functional p53 without a defect in p19/ARF (Guerra et al, 2003;Tuveson et al, 2004). Regarding this, it has been proposed that oncogenic K-Ras can suppress p53 (Halaschek-Weiner et al, 2004;Lee et al, 2009).…”

“…However, we have not shown how Snail eliminates p53. We have already explored several possibilities, including MDM-2-mediated p53 degradation, transcriptional regulation, mitogen-activated protein kinase signaling engagement and autophagy (Lee et al, 2009). But these mechanisms would not be involved in K-Ras-mediated p53 suppression.…”