Apoptosis

, Volume 12, Issue 4, pp 635–655

Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis

  • Ernestina Saulle
  • Alessia Petronelli
  • Luca Pasquini
  • Eleonora Petrucci
  • Gualtiero Mariani
  • Mauro Biffoni
  • Gianluigi Ferretti
  • Giovanni Scambia
  • Pierluigi Benedetti-Panici
  • Francesco Cognetti
  • Robin Humphreys
  • Cesare Peschle
  • Ugo Testa
Article

DOI: 10.1007/s10495-006-0025-9

Cite this article as:
Saulle, E., Petronelli, A., Pasquini, L. et al. Apoptosis (2007) 12: 635. doi:10.1007/s10495-006-0025-9

Abstract

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.

Keywords

Ovarian cancer Protesome inhibitors TRAIL Cell death receptos BH3 only proteins 

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ernestina Saulle
    • 1
  • Alessia Petronelli
    • 1
  • Luca Pasquini
    • 1
  • Eleonora Petrucci
    • 1
  • Gualtiero Mariani
    • 1
  • Mauro Biffoni
    • 1
  • Gianluigi Ferretti
    • 2
  • Giovanni Scambia
    • 3
  • Pierluigi Benedetti-Panici
    • 4
  • Francesco Cognetti
    • 2
  • Robin Humphreys
    • 5
  • Cesare Peschle
    • 1
  • Ugo Testa
    • 1
  1. 1.Medical Oncology Section, Department of Hematology, Oncology and Molecular MedicineIstituto Superiore di SanitàRomeItaly
  2. 2.Department of Medical OncologyRegina Elena Cancer InstituteRomeItaly
  3. 3.Department of OncologyCatholic UniversityCampobassoItaly
  4. 4.Institute of GynecologyPerinatalogy and Child Health, University “La Sapienza” of RomeRomeItaly
  5. 5.Department of Oncology ResearchHuman genome sciences Inc.RockvilleUSA