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Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4

Ravshan Burikhanov1, Tripti Shrestha-Bhattarai2, Nikhil Hebbar2

  • 1Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.

Cell Reports
|January 14, 2014
PubMed

Insights

Activating the guardian of the genome, p53, in normal cells triggers the secretion of tumor suppressor Par-4. This paracrine effect selectively induces apoptosis in p53-deficient cancer cells, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The tumor suppressor protein p53 is frequently mutated in various cancers, leading to therapeutic resistance.
  • Functional p53 in normal tissues presents an untapped resource for targeting p53-deficient tumors.

Purpose of the Study:

  • To investigate the potential of activating functional p53 in normal cells to inhibit the growth of p53-deficient cancer cells.
  • To elucidate the mechanism by which p53 activation in normal cells impacts cancer cells.

Main Methods:

  • Activation of p53 in normal human fibroblasts and mice.
  • Assessment of apoptosis induction in p53-deficient cancer cells.
  • Measurement of Par-4 secretion and UACA expression.
  • Studies in p53- and Par-4-deficient mouse models.

Main Results:

  • Specific activation of p53 in normal fibroblasts induced apoptosis in adjacent p53-deficient cancer cells via a paracrine mechanism.
  • This effect was mediated by the p53-dependent secretion of the tumor suppressor Par-4.
  • Systemic p53 activation in mice led to elevated Par-4 levels and apoptosis of p53-deficient tumors, dependent on functional p53 and Par-4.
  • p53 suppressed UACA expression, a Par-4 binding partner, thereby promoting Par-4 secretion.

Conclusions:

  • Normal cells, when their p53 is activated, can secrete Par-4 to inhibit p53-deficient tumors.
  • This p53-mediated induction of Par-4 secretion represents a potential therapeutic strategy against therapy-resistant cancers.

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