Poly(ADP-Ribose) Polymerase Inhibitors Sensitize Cancer Cells to Death Receptor-Mediated Apoptosis by Enhancing Death Receptor Expression [Signal Transduction]
June 3rd, 2014 by Meng, X. W., Koh, B. D., Zhang, J.-S., Flatten, K. S., Schneider, P. A., Billadeau, D. D., Hess, A. D., Smith, B. D., Karp, J. E., Kaufmann, S. H.
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 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 TNFR10B (DR5) promoters, increased Fas and DR5 mRNA, and elevated cell surface expression of these receptors in sensitized cells. 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. 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.