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Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation

Emma Hernlund1, Ozgur Kutuk, Huveyda Basaga

  • 1Department of Oncology-Pathology, CCK, Karolinska Institute, S-17176 Stockholm, Sweden.

Free Radical Biology & Medicine
|March 31, 2009
PubMed

Insights

Oxaliplatin, unlike cisplatin, triggers p53 mitochondrial translocation via nitrosative modification. This modification, influenced by inducible nitric oxide synthase (iNOS), dictates p53

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • DNA damage response involves p53 translocation to mitochondria.
  • The anticancer drugs cisplatin and oxaliplatin have distinct cellular effects.

Purpose of the Study:

  • To investigate the differential effects of oxaliplatin and cisplatin on p53 subcellular localization.
  • To elucidate the role of nitrosative modification in p53 mitochondrial translocation.

Main Methods:

  • Cellular treatment with oxaliplatin and cisplatin.
  • Assessment of p53 mitochondrial translocation and Bcl-xL interaction.
  • Analysis of inducible nitric oxide synthase (iNOS) expression and activity.
  • Investigation of nitrosative protein modification (nitrotyrosinylation).

Main Results:

  • Oxaliplatin induced p53 mitochondrial translocation and Bcl-xL interaction; cisplatin did not.
  • Differential response attributed to nitrosative modification of p53.
  • Cisplatin, but not oxaliplatin, increased iNOS expression.
  • iNOS inhibition restored oxaliplatin-induced p53 translocation, while NO donation blocked it.
  • Nitrotyrosinylation of p53 was observed in cisplatin-treated cells.

Conclusions:

  • Nitrosative protein modification plays a key role in the cellular response to DNA-damaging agents.
  • Nitrosative modification of p53 is a critical determinant of its subcellular localization.
  • Distinct mechanisms govern p53 translocation in response to cisplatin versus oxaliplatin.

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