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

Aberrant Wnt/beta-catenin signaling contributes to the development of many cancers, including glial tumorigenesis. While cross talk between the Wnt/beta-catenin and PI3K/AKT signaling pathways has been proposed, the impact of PI3K/AKT inhibition on beta-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 beta-catenin pathway, including Fra-1, c-Myc, and cyclin D1. Downregulation impacted beta-catenin-mediated transcription, as LY294002 decreased beta-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 beta-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/beta-catenin pathway. (C) 2010 Elsevier B.V. All rights reserved.