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


METHODS
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.
Guerreiro
Ana S
AS
Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
Fattet
Sarah
S
Fischer
Barbara
B
Shalaby
Tarek
T
Jackson
Shaun P
SP
Schoenwaelder
Simone M
SM
Grotzer
Michael A
MA
Delattre
Olivier
O
Arcaro
Alexandre
A
D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034622:RNA Interference; D015398:Signal Transduction
D058534:Class I Phosphatidylinositol 3-Kinases; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C497132:PIK3CB protein, human