Poly(ADP-ribose) Polymerase Inhibitors Sensitize Cancer Cells to Death Receptor-Mediated Apoptosis by Enhancing Death Receptor Expression

摘要: Recombinant human tumor necrosis factor-α-related apoptosis inducing ligand (TRAIL), agonistic monoclonal antibodies to TRAIL receptors, and small molecule receptor agonists are in various stages of preclinical early phase clinical testing as potential anticancer drugs. Accordingly, there is substantial interest understanding factors that affect sensitivity these agents. In the present study we observed poly(ADP-ribose) polymerase (PARP) inhibitors olaparib veliparib sensitize myeloid leukemia cell lines ML-1 K562, ovarian cancer line PEO1, non-small lung A549, a majority AML isolates, but not normal marrow, TRAIL. Further analysis demonstrated PARP inhibitor treatment results activation FAS TNFRSF10B (death 5 (DR5)) promoters, increased Fas DR5 mRNA, elevated surface expression receptors sensitized cells. Chromatin immunoprecipitation enhanced binding transcription factor Sp1 promoter presence inhibitor. Knockdown PARP1 or PARP2 (but PARP3 PARP4) only at mRNA protein level, also recapitulated sensitizing effects inhibition. Conversely, knockdown diminished effects. view fact part armamentarium natural killer cells, observations identify new facet action while simultaneously providing mechanistic underpinnings novel therapeutic combination warrants further investigation.