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MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells

A M Rodriguez-Lopez1, D Xenaki, T O Eden

  • 1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, U.K.

Molecular Pharmacology
|December 23, 2000
PubMed

Insights

Cytoplasmic accumulation of p53 protein in neuroblastoma suppresses chemotherapy-induced apoptosis but not growth arrest. Inhibiting MDM2 enhances etoposide efficacy by promoting apoptosis over trans-differentiation in neuroblastoma cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The p53 tumor suppressor protein is crucial for mediating chemotherapy's cytotoxic effects.
  • In neuroblastoma, p53 is rarely mutated but often accumulates in the cytoplasm, questioning its functional status.
  • Understanding p53's localization is key to deciphering its role in neuroblastoma treatment resistance.

Purpose of the Study:

  • To investigate whether cytoplasmic p53 accumulation impairs its function in neuroblastoma.
  • To determine the impact of p53 nuclear export on etoposide-induced apoptosis and growth arrest.
  • To explore the role of MDM2 in regulating p53 localization and chemosensitivity in neuroblastoma.

Main Methods:

  • Comparison of p53 function in two neuroblastoma subclones (SH-SY5Y and SH-EP1) with differing MDM2 levels.
  • Treatment with etoposide to assess apoptosis and growth arrest.
  • Inhibition of MDM2 expression using a phosphorothioated antisense oligonucleotide (AS5).
  • Analysis of p53 translocation, apoptosis, p21 induction, and G1-arrest.

Main Results:

  • Hyperactive nuclear export of p53 suppressed etoposide-induced apoptosis in SH-EP1 cells (high MDM2) but not growth arrest.
  • SH-SY5Y cells (low MDM2) showed nuclear p53 translocation and apoptosis upon etoposide treatment.
  • Inhibiting MDM2 in SH-EP1 cells restored nuclear p53 accumulation and induced apoptosis.
  • G1-arrest was not attenuated in S-type cells despite cytoplasmic p53, but was attenuated in N-type cells with high nuclear p53.

Conclusions:

  • Hyperactive nuclear export of p53 attenuates chemotherapy-induced apoptosis in neuroblastoma cells.
  • G1-arrest attenuation is linked to neuroblastoma differentiation status and occurs downstream of p53 nuclear accumulation.
  • MDM2 inhibitors may enhance etoposide efficacy by promoting apoptosis rather than trans-differentiation in neuroblastoma.

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