title: Poly(ADP-ribose) polymerase inhibitors sensitize cancer cells to death receptor-mediated apoptosis by enhancing death receptor expression.
abstract: Recombinant human tumor necrosis factor-α-related apoptosis inducing ligand (TRAIL), agonistic monoclonal antibodies to TRAIL receptors, and small molecule TRAIL receptor agonists are in various stages of preclinical and early phase clinical testing as potential anticancer drugs. Accordingly, there is substantial interest in understanding factors that affect sensitivity to these agents. In the present study we observed that the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and veliparib sensitize the myeloid leukemia cell lines ML-1 and K562, the ovarian cancer line PEO1, non-small cell lung cancer line A549, and a majority of clinical AML isolates, but not normal marrow, to TRAIL. Further analysis demonstrated that PARP inhibitor treatment results in activation of the FAS and TNFRSF10B (death receptor 5 (DR5)) promoters, increased Fas and DR5 mRNA, and elevated cell surface expression of these receptors in sensitized cells. Chromatin immunoprecipitation demonstrated enhanced binding of the transcription factor Sp1 to the TNFRSF10B promoter in the presence of PARP inhibitor. Knockdown of PARP1 or PARP2 (but not PARP3 and PARP4) not only increased expression of Fas and DR5 at the mRNA and protein level, but also recapitulated the sensitizing effects of the PARP inhibition. Conversely, Sp1 knockdown diminished the PARP inhibitor effects. In view of the fact that TRAIL is part of the armamentarium of natural killer cells, these observations identify a new facet of PARP inhibitor action while simultaneously providing the mechanistic underpinnings of a novel therapeutic combination that warrants further investigation.
authors.forename: X Wei
authors.initials: XW
authors.lastname: Meng
authors.forename: Brian D
authors.initials: BD
authors.lastname: Koh
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; C491901:FAS protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases