Cellular FLICE-inhibitory protein regulates chemotherapy-induced apoptosis in breast cancer cells.
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-gamma 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-gamma down-regulated the expression of the caspase-8 inhibitor cellular FLICE-inhibitory protein (c-FLIP). Furthermore, IFN-gamma 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-gamma had no effect on c-FLIP mRNA levels, indicating that c-FLIP was down-regulated at a posttranscriptional level following IFN-gamma 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-gamma- 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-gamma-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.
Rogers
Katherine M A
KM
Drug Resistance Laboratory, 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.
Thomas
Michelle
M
Galligan
Leeona
L
Wilson
Timothy R
TR
Allen
Wendy L
WL
Sakai
Hidekazu
H
Johnston
Patrick G
PG
Longley
Daniel B
DB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000502:physiology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D000077146:Irinotecan; D008942:Mitoxantrone / Q000494:pharmacology
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D005047:Etoposide; D000077146:Irinotecan; D007371:Interferon-gamma; D008942:Mitoxantrone; D053181:Caspase 8; D002166:Camptothecin