Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells
Data(s) |
01/05/2007
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Resumo |
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. |
Identificador |
http://dx.doi.org/10.1158/1535-7163.MCT-06-0673 http://www.scopus.com/inward/record.url?scp=34250730846&partnerID=8YFLogxK |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Rogers , K , Thomas , M , Johnston , P , Galligan , L , Wilson , T , Allen , W , Sakai , H & Longley , D 2007 , ' Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells ' Molecular Cancer Therapeutics , vol 6(5) , no. 5 , pp. 1544-1551 . DOI: 10.1158/1535-7163.MCT-06-0673 |
Palavras-Chave | #/dk/atira/pure/subjectarea/asjc/2700/2730 #Oncology #/dk/atira/pure/subjectarea/asjc/3000/3002 #Drug Discovery #/dk/atira/pure/subjectarea/asjc/3000/3004 #Pharmacology |
Tipo |
article |