Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor

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Ana S Guerreiro1, Danielle Boller, Tarek Shalaby

  • 1Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland.

International Journal of Cancer
|September 22, 2006
PubMed

Insights

The novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 effectively reduces neuroblastoma cell growth. Combining NVP-AEW541 with Akt/PKB inhibitors or chemotherapy may offer a new treatment strategy for neuroblastoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Neuroblastoma is a pediatric cancer with limited treatment options.
  • Insulin-like growth factor receptor (IGF-IR) signaling promotes cancer cell proliferation.
  • Targeting IGF-IR is a potential therapeutic strategy for neuroblastoma.

Purpose of the Study:

  • To investigate the antiproliferative potential of the IGF-IR inhibitor NVP-AEW541 in human neuroblastoma.
  • To elucidate the mechanisms underlying neuroblastoma cell sensitivity and resistance to NVP-AEW541.
  • To explore combination therapies involving NVP-AEW541.

Main Methods:

  • Assessed NVP-AEW541's effect on neuroblastoma cell proliferation using IC50 values.
  • Utilized IGF-IR neutralizing antibodies to confirm receptor dependence.
  • Investigated the role of Akt/protein kinase B (PKB) and ribosomal S6 protein phosphorylation in drug sensitivity.
  • Examined the impact of Akt/PKB and S6K modulation on NVP-AEW541 sensitivity.
  • Evaluated NVP-AEW541's effect on IGF-I-stimulated proliferation and cisplatin-induced apoptosis.

Main Results:

  • NVP-AEW541 inhibited proliferation of neuroblastoma cell lines with IC50 values from 0.15 to 5 microM.
  • IGF-IR was essential for neuroblastoma cell growth; its expression level did not correlate with sensitivity.
  • Coexpression of IGF-IR and insulin receptor (IR) correlated with lower sensitivity in some cell lines.
  • High Akt/PKB activation and S6 protein phosphorylation were linked to decreased sensitivity.
  • Inhibition of Akt/PKB restored sensitivity, while Akt or S6K activation decreased it.
  • NVP-AEW541 blocked IGF-I-stimulated proliferation and sensitized cells to cisplatin-induced apoptosis.

Conclusions:

  • NVP-AEW541 demonstrates significant antiproliferative activity against human neuroblastoma.
  • Akt/PKB signaling pathways play a crucial role in mediating resistance to NVP-AEW541.
  • Combination therapy with NVP-AEW541 and Akt/PKB inhibitors or chemotherapeutic agents shows promise for neuroblastoma treatment.

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