Scientific article

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

Published inHuman pathology, vol. 42, no. 11, p. 1727-1739
Publication date2011

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.

  • Cell Cycle Checkpoints/drug effects
  • Cell Line, Tumor
  • Chromones/pharmacology
  • Doxorubicin/pharmacology
  • Enzyme Activation
  • 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
Citation (ISO format)
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. 1727–1739. doi: 10.1016/j.humpath.2011.01.019
Main files (1)
Article (Published version)
ISSN of the journal0046-8177

Technical informations

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