PI3K p110β isoform synergizes with JNK in the regulation of glioblastoma cell proliferation and migration through Akt and FAK inhibitionReportar como inadecuado




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Journal of Experimental and Clinical Cancer Research

, 35:78

First Online: 12 May 2016Received: 26 January 2016Accepted: 03 May 2016DOI: 10.1186-s13046-016-0356-5

Cite this article as: Zhao, HF., Wang, J., Jiang, HR. et al. J Exp Clin Cancer Res 2016 35: 78. doi:10.1186-s13046-016-0356-5

Abstract

BackgroundGlioblastoma multiforme is the most aggressive malignant primary brain tumor, characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Both PI3K-Akt and JNK pathways are essential to glioblastoma cell survival, migration and invasion. Due to their hyperactivation in glioblastoma cells, PI3K and JNK are promising targets for glioblastoma treatment.

MethodsTo investigate the combination effects of class IA PI3K catalytic isoforms p110α, p110β and p110δ and JNK inhibition on tumor cell growth and motility, glioblastoma cells and xenografts in nude mice were treated with isoform-selective PI3K inhibitors in combination with JNK inhibitor.

ResultsWe showed that combined inhibition of these PI3K isoforms and JNK exerted divergent effects on the proliferation, migration and invasion of glioblastoma cells in vitro. Pharmacological inhibition of p110β or p110δ, but not p110α, displayed synergistic inhibitory effect with JNK inhibition on glioblastoma cell proliferation and migration through decreasing phosphorylation of Akt, FAK and zyxin, leading to blockade of lamellipodia and membrane ruffles formation. No synergistic effect on invasion was observed in all the combination treatment. In vivo, combination of p110β and JNK inhibitors significantly reduced xenograft tumor growth compared with single inhibitor alone.

ConclusionConcurrent inhibition of p110β and JNK exhibited synergistic effects on suppressing glioblastoma cell proliferation and migration in vitro and xenograft tumor growth in vivo. Our data suggest that combined inhibition of PI3K p110β isoform and JNK may serve as a potent and promising therapeutic approach for glioblastoma multiforme.

KeywordsGlioblastoma PI3K p110β JNK Synergism Proliferation Migration AbbreviationsAP-1transcription factor activator protein-1

BSAbovine serum albumin

CIcombination index

DMSOdimethyl sulfoxide

EGFRepidermal growth factor receptor

Ena-VASPenabled-vasodilator-stimulated phospho-protein

FAfraction affected

FAKfocal adhesion kinase

FBSfetal bovine serum

GBMglioblastoma multiforme

GPCRG protein–coupled receptor

JNK c-JunN-terminal kinase

MEFmouse embryonic fibroblast

MEKmitogen-extracellular activated protein kinase

MKK4mitogen-activated protein kinase kinase 4

MTT3-4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide

NSCLCnon-small cell lung carcinoma

PDK1phosphoinositide-dependent kinase 1

PI3Kphosphatidylinositol 3-kinase

RTKreceptor tyrosine kinase

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-016-0356-5 contains supplementary material, which is available to authorized users.

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Autor: Hua-Fu Zhao - Jing Wang - Hao-Ran Jiang - Zhong-Ping Chen - Shing-Shun Tony To

Fuente: https://link.springer.com/







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