Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration.

Details

Serval ID
serval:BIB_8B519979ADBC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration.
Journal
Clinical Cancer Research
Author(s)
Guerreiro A.S., Fattet S., Fischer B., Shalaby T., Jackson S.P., Schoenwaelder S.M., Grotzer M.A., Delattre O., Arcaro A.
ISSN
1078-0432
Publication state
Published
Issued date
2008
Volume
14
Number
21
Pages
6761-6769
Language
english
Abstract
PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha, p110beta, or p110delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors. RESULTS: Overexpression of the catalytic p110alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110alpha expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110beta or p110delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110alpha inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110alpha in medulloblastoma growth and survival.
Keywords
1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors, 1-Phosphatidylinositol 3-Kinase/metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Down-Regulation, Drug Delivery Systems, Drug Resistance, Neoplasm, Humans, Isoenzymes/antagonists & inhibitors, Isoenzymes/metabolism, Medulloblastoma/metabolism, Medulloblastoma/pathology, RNA Interference, Signal Transduction
Pubmed
Web of science
Open Access
Yes
Create date
15/10/2009 8:14
Last modification date
20/08/2019 14:49
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