Inactivation of PI3K/AKT signaling inhibits glioma cell growth through modulation of β-catenin-mediated transcription

Brain Res. 2010 Dec 17;1366:9-17. doi: 10.1016/j.brainres.2010.09.097. Epub 2010 Oct 1.

Abstract

Aberrant Wnt/β-catenin signaling contributes to the development of many cancers, including glial tumorigenesis. While cross talk between the Wnt/β-catenin and PI3K/AKT signaling pathways has been proposed, the impact of PI3K/AKT inhibition on β-catenin signaling in glioma remains unknown. In the present study, we report decreased cell proliferation and invasive ability upon the LY294002-induced inhibition of PI3K in both U251 and LN229 human glioblastoma cells in vitro. Pharmacologic inhibition of PI3K resulted in the downregulation of several members of the β-catenin pathway, including Fra-1, c-Myc, and cyclin D1. Downregulation impacted β-catenin-mediated transcription, as LY294002 decreased β-catenin/TCF transcriptional activity, determined by the reporter assay. Similar results were observed in vivo, as intratumoral injection of LY294002 downregulated the expression of the components of the β-catenin pathway and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts. These results suggest that the PI3K/AKT signaling pathway regulates glioma cell proliferation, in part via repression of the Wnt/β-catenin pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Chromones / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / physiopathology*
  • Glioma / therapy
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Morpholines / pharmacology
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Serine / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Time Factors
  • Transfection / methods
  • beta Catenin / metabolism*

Substances

  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • beta Catenin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serine
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt