Journal Article

Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3β pathway in colon cancer

Ashok Kumar, Ashok K. Pandurangan, Fang Lu, Henrik Fyrst, Meng Zhang, Hoe-Sup Byun, Robert Bittman and Julie D. Saba

in Carcinogenesis

Volume 33, issue 9, pages 1726-1735
Published in print September 2012 | ISSN: 0143-3334
Published online May 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs174
Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3β pathway in colon cancer

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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.

Abbreviations:

4EBP-1

eIF4E-binding protein1

APC

adenomatous polyposis coli

GSK3β

Glycogen synthase Kinase 3β

LCM

laser capture microscopy

LEF

lymphoid enhancer factor

mTOR

mammalian target of Rapamycin

PI3K

Phosphatidylinositol-3-kinase

PKC

protein kinase C

PP2A

protein phosphatase 2A

TCF

T-cell factor

SD

Sphingadiene

Journal Article.  6342 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.