Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3β pathway in colon cancer
Menée in vitro et à l'aide d'un modèle murin, cette étude montre que les sphingosines ont un effet chimiopréventif sur la tumorigenèse du côlon en inhibant la signalisation Wnt par un mécanisme impliquant la voie PP2A/Akt/GSK3β
Sphingadienes derived from soy and other natural sphingolipids are cytotoxic to colon cancer cells via an Akt-dependent mechanism and reduce adenoma formation in ApcMin/+ mice. Wnt signaling is fundamental to colon carcinogenesis and is the basis for spontaneous tumorigenesis in ApcMin/+ mice and patients with familial adenomatous polyposis. In the present study, we investigated the impact of sphingadienes on Wnt signaling. Oral sphingadiene administration reduced levels of active β-catenin and Wnt targets c-Myc and cyclin D1 in ApcMin/+ mouse intestinal tissues. Colon cancer cells treated with sphingadienes exhibited reduced Wnt transcriptional activity, as well as reduced nuclear β-catenin localization and subsequent reduction in active-β-catenin levels. Further, we observed a decrease in phosphorylated (inactive) GSK3β in sphingadiene-treated mice and colon cancer cells. Expression of constitutively active myristoylated-Akt or inactivation of GSK3β using LiCl attenuated sphingadiene-mediated inhibition of Wnt transcriptional activity and active-β-catenin levels. Sphingadienes exhibited additive effects with inhibitors of the phosphatidylinositol-3-kinase/Akt/mTOR pathway to induce cytotoxicity. Further, a combination regime of sphingadienes and low-dose rapamycin decreased visible polyps in ApcMin/+ mice and reduced the levels of Wnt target gene expression and mTOR target activation. Sphingadiene-mediated inhibition of Akt and Wnt pathways and cytotoxicity in colon cancer cells was dependent upon the activity of protein phosphatase 2A, as shown by reversal of these effects by pretreatment with okadaic acid or calyculin A. Our cumulative findings indicate that sphingadienes inhibit Wnt signaling through a protein phosphatase 2A/Akt/GSK3β-dependent mechanism that may contribute to their chemopreventive effects in intestinal tumorigenesis.
http://carcin.oxfordjournals.org/content/early/2012/05/11/carcin.bgs174.abstract 2012