Inactivation of PI3K/AKT signaling inhibits glioma cell growth through modulation of β-catenin-mediated transcription.
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.
Han
Lei
L
Department of Neurosurgery, Laboratory of Neuro-Oncology, Tianjin Medical University General Hospital, Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government 300052, China.
Yang
Yang
Y
Yue
Xiao
X
Huang
Kai
K
Liu
Xiaomin
X
Pu
Peiyu
P
Jiang
Hao
H
Yan
Wei
W
Jiang
Tao
T
Kang
Chunsheng
C
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D051176:beta Catenin / Q000378:metabolism*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt