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Research Articles: Therapeutics, Targets, and Development

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

Drug Resistance Laboratory, Centre for Cancer Research and Cell Biology, The Queen's University of Belfast, Belfast City Hospital, Belfast, Northern Ireland

Requests for reprints: Daniel B. Longley, Centre for Cancer Research and Cell Biology, The Queen's University of Belfast, University Floor, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland. Phone: 44-28-90972636; Fax: 44-28-90263744. E-mail: d.longley{at}qub.ac.uk

Abstract

Combination treatment regimens that include topoisomerase-II–targeted drugs, such as doxorubicin, are widely used in the treatment of breast cancer. Previously, we showed that IFN- and doxorubicin cotreatment synergistically induced apoptosis in MDA435 breast cancer cells in a signal transducer and activator of transcription 1–dependent manner. In this study, we found that this synergy was caspase-8 dependent. In addition, we found that IFN- down-regulated the expression of the caspase-8 inhibitor cellular FLICE-inhibitory protein (c-FLIP). Furthermore, IFN- down-regulated c-FLIP in a manner that was dependent on the transcription factors signal transducer and activator of transcription 1 and IFN regulatory factor-1. However, IFN- had no effect on c-FLIP mRNA levels, indicating that c-FLIP was down-regulated at a posttranscriptional level following IFN- treatment. Characterization of the functional significance of c-FLIP modulation by small interfering RNA gene silencing and stable overexpression studies revealed it to be a key regulator of IFN-– 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 sensitized 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. [Mol Cancer Ther 2007;6(5):1544–51]

Grant support: Cancer Research UK, the Medical Research Council, the Northern Ireland Research and Development Office, and the Ulster Cancer Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/30/06; revised 2/16/07; accepted 3/23/07.

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