title: Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21(WAF-1/Cip-1) (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50% in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAIL and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy.
authors.affiliation: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Lashinger
authors.forename: Keyi
authors.initials: K
authors.lastname: Zhu
authors.forename: Simon A
authors.initials: SA
authors.lastname: Williams
authors.forename: Marissa
authors.initials: M
authors.lastname: Shrader
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008562:Membrane Glycoproteins; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases