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Activation of the phosphatidylinositol 3'-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1

Sartelet, Hervé
Fabre, Monique
Castaing, Marine
Duval, Michel
Fetni, Raouf
Michiels, Stefan
Beaunoyer, Mona
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Published in Human pathology. 2011, vol. 42, no. 11, p. 1727-39
Abstract Neuroblastoma is a malignant pediatric tumor with poor survival. The phosphatidylinositol 3'-kinase/AKT pathway is a crucial regulator of cellular processes including apoptosis. Thioredoxin 1, an inhibitor of tumor-suppressor phosphatase and tensin homolog, is overexpressed in many tumors. The objective of this study was to explore phosphatidylinositol 3'-kinase/AKT pathway activation and regulation by thioredoxin 1 to identify potential therapeutic targets. Immunohistochemical analysis was done on tissue microarrays from tumor samples of 101 patients, using antibodies against phosphatidylinositol 3'-kinase, AKT, activated AKT, phosphatase and tensin homolog, phosphorylated phosphatase and tensin homolog, thioredoxin 1, epidermal growth factor receptor, vascular endothelial growth factor and receptors (vascular endothelial growth factor 1 and vascular endothelial growth receptor 2), platelet-derived growth factor receptors, insulin-like growth factor 1 receptor, neurotrophic tyrosine kinase receptor type 2, phosphorylated 70-kd S6 protein kinase, 4E-binding protein 1, and phosphorylated mammalian target of rapamycin. Using 3 neuroblastoma cell lines, we investigated cell viability with AKT-specific inhibitors (LY294002, RAD001) and thioredoxin 1 alone or in combination. We found activated AKT and AKT expressed in 97% and 98%, respectively, of neuroblastomas, despite a high expression of phosphatase and tensin homolog correlated with thioredoxin 1. AKT expression was greater in metastatic than primary tumors. Insulin-like growth factor 1 receptor, tyrosine kinase receptor type 2, vascular endothelial growth receptor 1, and downstream phosphorylated 70-kd S6 protein kinase were correlated with activated AKT. LY294002 and RAD001 significantly reduced AKT activity and cell viability and induced a G(1) cell cycle arrest. Thioredoxin 1 decreased cytotoxicity of AKT inhibitors and doxorubicin, up-regulated AKT activation, and induced cell growth. Thus, vascular endothelial growth receptor 1, tyrosine kinase receptor type 2, insulin-like growth factor 1 receptor, and thioredoxin 1 emerged as preferentially committed to phosphatidylinositol 3'-kinase/AKT pathway activation as observed in neuroblastoma. Thioredoxin 1 is a potential target for therapeutic intervention.
Keywords Cell Cycle Checkpoints/drug effectsCell Line, TumorChromones/pharmacologyDoxorubicin/pharmacologyEnzyme ActivationHumansInfantMorpholines/pharmacologyNeuroblastoma/physiopathology/secondaryPTEN Phosphohydrolase/metabolismPhosphatidylinositol 3-Kinase/metabolismProto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolismSirolimus/analogs & derivatives/pharmacologyThioredoxins/physiologyVascular Endothelial Growth Factor A/metabolism
PMID: 21641013
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SARTELET, Hervé et al. Activation of the phosphatidylinositol 3'-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1. In: Human pathology, 2011, vol. 42, n° 11, p. 1727-39. doi: 10.1016/j.humpath.2011.01.019 https://archive-ouverte.unige.ch/unige:25957

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Deposited on : 2013-01-28

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