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

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.

• Authors: Hervé Sartelet, Anne-Laure Rougemont, Monique Fabre, Marine Castaing, Michel Duval, Raouf Fetni, Stefan Michiels, Mona Beaunoyer, Gilles Vassal
• Journal: Human pathology (Hum Pathol) Vol. 42 Issue 11 Pg. 1727-39 (Nov 2011) ISSN: 1532-8392 [Electronic] United States
• PMID: 21641013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Chromones
• Morpholines
• Vascular Endothelial Growth Factor A
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Thioredoxins
• Doxorubicin
• Everolimus
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Sirolimus

Topics

• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Chromones (pharmacology)
• Doxorubicin (pharmacology)
• Enzyme Activation
• Everolimus
• Humans
• Infant
• Morpholines (pharmacology)
• Neuroblastoma (physiopathology, secondary)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Sirolimus (analogs & derivatives, pharmacology)
• Thioredoxins (physiology)
• Vascular Endothelial Growth Factor A (metabolism)