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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)635-655
Number of pages21
JournalApoptosis
Volume12
Issue number4
DOIs
Publication statusPublished - Apr 2007

Keywords

  • BH3 only proteins
  • Cell death receptos
  • Ovarian cancer
  • Protesome inhibitors
  • TRAIL

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cell Biology

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  • Cite this

    Saulle, E., Petronelli, A., Pasquini, L., Petrucci, E., Mariani, G., Biffoni, M., Ferretti, G., Scambia, G., Benedetti-Panici, P., Cognetti, F., Humphreys, R., Peschle, C., & Testa, U. (2007). Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis. Apoptosis, 12(4), 635-655. https://doi.org/10.1007/s10495-006-0025-9