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A human ribonuclease induces apoptosis associated with p21WAF1/CIP1 induction and JNK inactivation

Jessica Castro1, Marc Ribó, Susanna Navarro

  • 1Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi s/n E-17071 Girona, Spain.

BMC Cancer
|January 13, 2011
PubMed
Abstract

Insights

PE5, a ribonuclease variant, induces cancer cell death via apoptosis, independent of p53 and drug resistance. Its mechanism differs from onconase, involving cell cycle arrest and JNK inactivation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Ribonucleases are investigated as anticancer agents.
  • Onconase, a ribonuclease, shows cytotoxic and cytostatic effects and is in clinical trials.
  • PE5, a human pancreatic ribonuclease variant with a nuclear localization signal, is studied for its anticancer potential.

Purpose of the Study:

  • To investigate and compare the cytotoxicity mechanisms of PE5 and onconase.
  • To elucidate the role of apoptosis, cell cycle, and specific protein pathways in PE5-induced cell death.

Main Methods:

  • Cytotoxicity assessed using MTT and trypan blue exclusion assays.
  • Apoptosis evaluated via flow cytometry, caspase activity detection, and confocal microscopy.
  • Cell cycle distribution and protein expression (cyclins, caspases, XIAP, JNK) analyzed by flow cytometry and western blot.

Main Results:

  • PE5 induces apoptosis independently of p53 and multidrug resistance.
  • Both PE5 and onconase exhibit similar cell death extent, but only onconase causes growth arrest.
  • PE5 treatment increases cells in S and G2/M phases, upregulates cyclin E and p21WAF1/CIP1, and inactivates JNK.
  • Onconase does not alter cell cycle distribution but decreases XIAP expression.

Conclusions:

  • PE5 mediates cancer cell death through apoptosis, p21WAF1/CIP1 induction, and JNK inactivation.
  • The cytotoxic mechanism of PE5 is distinct from that of onconase.
  • PE5 represents a promising anticancer agent with a unique mechanism of action.

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