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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific

Tadahisa Shono1, Philip J Tofilon, Timothy S Schaefer

  • 1Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

Cancer Research
|February 28, 2002
PubMed

Insights

Adenovirus-mediated p53 gene therapy (Ad-p53) shows promise for glioma treatment. Phosphorylation of p53 at serines 15 and 20 is crucial for inducing apoptosis in glioma cells, enhancing Ad-p53 therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Glioma treatment faces challenges with conventional therapies.
  • Adenovirus-mediated p53 gene therapy (Ad-p53) is a potential alternative.
  • Differential responses of mutant vs. wild-type p53 glioma cells to Ad-p53 require mechanistic understanding.

Purpose of the Study:

  • To investigate the role of p53 phosphorylation in Ad-p53-mediated apoptosis in glioma cells.
  • To elucidate the mechanism behind differential Ad-p53 responses in mutant and wild-type p53 glioma cells.
  • To assess the impact of p53 phosphorylation at serines 15, 20, and 392 on Ad-p53 therapy outcomes.

Main Methods:

  • Utilized glioma cell lines with mutant (U251, U373) and wild-type (U87, D54) p53.
  • Infected cells with Ad-p53 and analyzed exogenous p53 expression via Western blotting.
  • Assessed phosphorylation status of p53 at serines 15, 20, and 392.
  • Investigated apoptosis induction in response to Ad-p53 alone, combined with radiation, cisplatin, or BCNU.

Main Results:

  • High levels of exogenous p53 were detected in all infected glioma cells.
  • Apoptotic mutant p53 cells showed high levels of phospho-Ser15-p53 and phospho-Ser20-p53.
  • Wild-type p53 cells had low levels of phospho-p53 after Ad-p53 infection alone.
  • Combined Ad-p53 and radiation/chemotherapy significantly increased phospho-Ser15/20-p53 and apoptosis in wild-type cells.
  • Phosphorylation at Ser15 and Ser20 correlated with apoptosis levels; Ser15 mutation partially inhibited p53 apoptotic activity.

Conclusions:

  • Phosphorylation of p53 at serine 15 and serine 20 is critical for Ad-p53-induced apoptosis in glioma.
  • This phosphorylation mechanism explains differential responses and enhances therapeutic efficacy of Ad-p53 in glioma.
  • Targeting p53 phosphorylation may optimize gene therapy strategies for glioma treatment.

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