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IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression.
- Source :
-
Cancer research [Cancer Res] 2009 Feb 01; Vol. 69 (3), pp. 1080-8. Date of Electronic Publication: 2009 Jan 20. - Publication Year :
- 2009
-
Abstract
- IFN regulatory factor 8 (IRF8) has been shown to suppress tumor development at least partly through regulating apoptosis of tumor cells; however, the molecular mechanisms underlying IRF8 regulation of apoptosis are still not fully understood. Here, we showed that disrupting IRF8 function resulted in inhibition of cytochrome c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase cleavage in soft tissue sarcoma (STS) cells. Inhibition of the mitochondrion-dependent apoptosis signaling cascade is apparently due to blockage of caspase-8 and Bid activation. Analysis of signaling events upstream of caspase-8 revealed that disrupting IRF8 function dramatically increases FLIP mRNA stability, resulting in increased IRF8 protein level. Furthermore, primary myeloid cells isolated from IRF8-null mice also exhibited increased FLIP protein level, suggesting that IRF8 might be a general repressor of FLIP. Nuclear IRF8 protein was absent in 92% (55 of 60) of human STS specimens, and 99% (59 of 60) of human STS specimens exhibited FLIP expression, suggesting that the nuclear IRF8 protein level is inversely correlated with FLIP level in vivo. Silencing FLIP expression significantly increased human sarcoma cells to both FasL-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and ectopic expression of IRF8 also significantly increased the sensitivity of these human sarcoma cells to FasL- and TRAIL-induced apoptosis. Taken together, our data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRF8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in human STS therapy.
- Subjects :
- Animals
Apoptosis drug effects
CASP8 and FADD-Like Apoptosis Regulating Protein genetics
Caspase 8 metabolism
Caspase Inhibitors
Cell Line, Tumor
Enzyme Activation
Fas Ligand Protein pharmacology
Humans
Immunohistochemistry
Mice
Mitochondria drug effects
RNA, Messenger biosynthesis
RNA, Messenger genetics
RNA, Small Interfering genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
Sarcoma drug therapy
Sarcoma genetics
Sarcoma pathology
Sarcoma, Experimental drug therapy
Sarcoma, Experimental genetics
Sarcoma, Experimental metabolism
Sarcoma, Experimental pathology
Apoptosis physiology
CASP8 and FADD-Like Apoptosis Regulating Protein biosynthesis
Interferon Regulatory Factors biosynthesis
Mitochondria physiology
Sarcoma metabolism
TNF-Related Apoptosis-Inducing Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 69
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 19155307
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-2520