title: Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3β pathway in colon cancer.
abstract: Sphingadienes (SDs) derived from soy and other natural sphingolipids are cytotoxic to colon cancer cells via an Akt-dependent mechanism and reduce adenoma formation in Apc(Min/+) mice. Wnt signaling is fundamental to colon carcinogenesis and is the basis for spontaneous tumorigenesis in Apc(Min/+) mice and patients with familial adenomatous polyposis. In the present study, we investigated the impact of SDs on Wnt signaling. Oral SD administration reduced levels of active β-catenin and Wnt targets c-Myc and cyclin D1 in Apc(Min/+) mouse intestinal tissues. Colon cancer cells treated with SDs 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 SD-treated mice and colon cancer cells. Expression of constitutively active myristoylated-Akt or inactivation of GSK3β using LiCl attenuated SD-mediated inhibition of Wnt transcriptional activity and active-β-catenin levels. SDs exhibited additive effects with inhibitors of the phosphatidylinositol-3-kinase/Akt/mTOR pathway to induce cytotoxicity. Further, a combination regime of SDs and low-dose rapamycin decreased visible polyps in Apc(Min/+) mice and reduced the levels of Wnt target gene expression and mTOR target activation. SD-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 SDs inhibit Wnt signaling through a protein phosphatase 2A/Akt/GSK3β-dependent mechanism that may contribute to their chemopreventive effects in intestinal tumorigenesis.
authors.affiliation: Center for Cancer Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Pandurangan
authors.forename: Fang
authors.initials: F
authors.lastname: Lu
authors.forename: Henrik
authors.initials: H
authors.lastname: Fyrst
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Hoe-Sup
authors.initials: HS
authors.lastname: Byun
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D054648:Protein Phosphatase 2 / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D020218:Response Elements; D015398:Signal Transduction; D013107:Sphingolipids / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology
chemical_list: D016588:Anticarcinogenic Agents; D013107:Sphingolipids; D016159:Tumor Suppressor Protein p53; D003577:Cytochrome P-450 Enzyme System; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2