title: The Deubiquitinase Inhibitor PR-619 Sensitizes Normal Human Fibroblasts to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Cell Death.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapy that selectively targets cancer cell death while non-malignant cells remain viable. Using a panel of normal human fibroblasts, we characterized molecular differences in human foreskin fibroblasts and WI-38 TRAIL-resistant cells and marginally sensitive MRC-5 cells compared with TRAIL-sensitive human lung and colon cancer cells. We identified decreased caspase-8 protein expression and protein stability in normal fibroblasts compared with cancer cells. Additionally, normal fibroblasts had incomplete TRAIL-induced caspase-8 activation compared with cancer cells. We found that normal fibroblasts lack the ubiquitin modification of caspase-8 required for complete caspase-8 activation. Treatment with the deubiquitinase inhibitor PR-619 increased caspase-8 ubiquitination and caspase-8 enzymatic activity and sensitized normal fibroblasts to TRAIL-mediated apoptosis. Therefore, posttranslational regulation of caspase-8 confers resistance to TRAIL-induced cell death in normal cells through blockade of initiation of the extrinsic cell death pathway.
authors.affiliation: From the Department of Medicine, Hematology/Oncology Division, Penn State Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, Pennsylvania 17033 and.
authors.forename: Roslyn N
authors.initials: RN
authors.lastname: Crowder
authors.affiliation: From the Department of Medicine, Hematology/Oncology Division, Penn State Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, Pennsylvania 17033 and; the Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.affiliation: From the Department of Medicine, Hematology/Oncology Division, Penn State Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, Pennsylvania 17033 and; the Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. Electronic address: wafik.eldeiry@fccc.edu.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013861:Thiocyanates / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: C570894:2,6-diaminopyridine-3,5-bis(thiocyanate); D000631:Aminopyridines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013861:Thiocyanates; D053181:Caspase 8
keywords: TRAIL; caspase; cell death; deubiquitylation (deubiquitination); fibroblast