title: A novel kinase inhibitor of FADD phosphorylation chemosensitizes through the inhibition of NF-κB.
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.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Schinske
authors.forename: Shyam
authors.initials: S
authors.lastname: Nyati
authors.forename: Amjad P
authors.initials: AP
authors.lastname: Khan
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Johnson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Ricardo Pérez
authors.initials: RP
authors.lastname: Tomás
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014157:Transcription Factors; D002945:Cisplatin