Abstract:
:Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-κB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1α. NSC 47147 was shown to decrease levels of p-FADD and NF-κB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell-based assays for the identification of active compounds and the validation of drug-target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Schinske KA,Nyati S,Khan AP,Williams TM,Johnson TD,Ross BD,Tomás RP,Rehemtulla Adoi
10.1158/1535-7163.MCT-11-0362subject
Has Abstractpub_date
2011-10-01 00:00:00pages
1807-17issue
10eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-11-0362journal_volume
10pub_type
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