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ASK1 resistant neuroblastoma is deficient in activation of p38 kinase

Y Arvidsson1, T S Hamazaki, H Ichijo

  • 1Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Göteborg University, Box 420, SE-405 30 Gothenburg, Sweden. yvonne.avidsson@anatcell.gu.se

Cell Death and Differentiation
|October 13, 2001
PubMed

Insights

Apoptosis Signal-regulating Kinase 1 (ASK1) induces apoptosis in neuroblastoma cells primarily through the p38 MAPK pathway. Paclitaxel can sensitize resistant neuroblastoma cells to ASK1-induced cell death.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Apoptosis Signal-regulating Kinase 1 (ASK1) plays a dual role in neuronal cells, potentially inducing apoptosis or differentiation.
  • Neuroblastoma, a common childhood cancer, exhibits varied responses to cellular stress and signaling pathways.

Purpose of the Study:

  • To investigate the role of constitutively active ASK1 (ASK1-Delta N) in inducing apoptosis across different neuroblastoma cell lines.
  • To elucidate the specific signaling pathways involved in ASK1-mediated apoptosis in neuroblastoma.
  • To explore strategies for sensitizing resistant neuroblastoma cells to ASK1-induced apoptosis.

Main Methods:

  • Adenoviral delivery of ASK1-Delta N into murine (C1300, NXS2) and human (SH-SY5Y, IMR-32) neuroblastoma cell lines.
  • Assessment of cell growth inhibition using [(3)H]thymidine incorporation and apoptosis via DNA laddering.
  • Analysis of p38 MAPK and JNK activation using immunoblotting.
  • Inhibition studies using the p38 MAPK specific inhibitor SB203580.
  • Sensitization experiments with the anti-neoplastic agent paclitaxel.

Main Results:

  • ASK1-Delta N induced growth arrest and apoptosis in C1300 and SH-SY5Y cells, but not in NXS2 and IMR-32 cells.
  • Apoptosis in sensitive cells correlated with strong p38 MAPK and weak JNK phosphorylation.
  • The p38 MAPK inhibitor SB203580 protected C1300 and SH-SY5Y cells from ASK1-induced apoptosis.
  • Paclitaxel sensitized the resistant NXS2 cell line to ASK1-induced cell death.

Conclusions:

  • ASK1 primarily induces apoptosis in neuroblastoma cells via the p38 MAPK signaling pathway.
  • Neuroblastoma cell line resistance to ASK1-induced apoptosis can be overcome by paclitaxel treatment.
  • These findings highlight potential therapeutic strategies targeting ASK1 and p38 MAPK in neuroblastoma treatment.

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