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Reactive oxygen species-mediated p53 core-domain modifications determine apoptotic or necrotic death in cancer cells

Rajan Gogna1, Esha Madan, Periannan Kuppusamy

  • 1Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.

Antioxidants & Redox Signaling
|December 8, 2011
PubMed
Abstract

Insights

Gold nanoparticles (Au-NPs) trigger p53-dependent apoptosis and necrosis in cancer cells. Differential reactive oxygen species (ROS) patterns dictate p53 modifications, leading to distinct downstream gene activation and tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nanotechnology

Background:

  • The tumor suppressor p53 plays a critical role in cellular stress responses, inducing apoptosis or necrosis.
  • The precise molecular mechanisms governing p53's choice between apoptotic and necrotic cell death pathways remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying p53's decision to induce either apoptosis or necrosis.
  • To investigate the role of gold nanoparticles (Au-NPs) in modulating p53-mediated cell death pathways.

Main Methods:

  • Utilized gold nanoparticles (Au-NPs) to induce cell death in cancer cells.
  • Analyzed differential reactive oxygen species (ROS) generation patterns.
  • Assessed p53 post-translational modifications (phosphorylation and acetylation) and DNA-binding activity.
  • Quantified the activation of distinct sets of p53-downstream genes.
  • Evaluated tumor regression in a mouse xenograft model.

Main Results:

  • Au-NPs induced both apoptosis and necrosis in a p53-dependent manner.
  • Differential ROS generation correlated with distinct p53 post-translational modification patterns (core-domain for apoptosis, N- and C-termini for necrosis).
  • Specific Au-NP formulations (Au-NP10 and Au-NP80) activated distinct sets of apoptotic and necrotic p53-downstream genes.
  • Both Au-NP formulations demonstrated significant tumor regression in HCT (p53+/+) xenografts.

Conclusions:

  • Au-NP-mediated p53 activation, modulated by ROS and distinct post-translational modification patterns, drives tumor regression via both apoptotic and necrotic pathways.
  • This highlights the potential of nanoparticles in cancer therapy by targeting specific p53-mediated cell death mechanisms.

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