Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells

Katherine Rogers, M. Thomas, Patrick Johnston, L. Galligan, Timothy Wilson, Wendy Allen, Hidekazu Sakai, Daniel Longley

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Combination treatment regimens that include topoisomerase-II-targeted drugs, such as doxorubicin, are widely used in the treatment of breast cancer. Previously, we demonstrated that IFN-� and doxorubicin co-treatment synergistically induced apoptosis in MDA435 breast cancer cells in a STAT1-dependent manner. In this study, we found that this synergy was caspase 8-dependent. In addition, we found that IFN-γ down-regulated the expression of the caspase 8 inhibitor c-FLIP. Furthermore, IFN-� down-regulated c-FLIP in a manner that was dependent on the transcription factors STAT1 and IRF1. However, IFN-� had no effect on c-FLIP mRNA levels, indicating that c-FLIP was down-regulated at a post-transcriptional level following IFN-� treatment. Characterisation of the functional significance of c-FLIP modulation by siRNA gene silencing and stable over-expression studies, revealed it to be a key regulator of IFN-γ- and doxorubicin-induced apoptosis in MDA435 cells. Analysis of a panel of breast cancer cell lines indicated that c-FLIP was an important general determinant of doxorubicin- and IFN-�-induced apoptosis in breast cancer cells. Furthermore, c-FLIP gene silencing sensitised MDA435 cells to other chemotherapies, including etoposide, mitoxantrone and SN-38. These results suggest that c-FLIP plays a pivotal role in modulating drug-induced apoptosis in breast cancer cells.
Original languageEnglish
Pages (from-to)1544-1551
Number of pages8
JournalMolecular Cancer Therapeutics
Volume6(5)
Issue number5
DOIs
Publication statusPublished - 01 May 2007

Bibliographical note

Five-year impact factor = 5.720

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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