Elevated poly-(ADP-ribose)-polymerase activity sensitizes retinoblastoma-deficient cells to DNA damage-induced necrosis.
The retinoblastoma (Rb) tumor suppressor is a key regulator of cell cycle checkpoints but also protects against cell death induced by stresses such as DNA damage and death receptor ligation. We report here that cell death of Rb-deficient cells exposed to key genotoxic agents was associated with increased expression of S phase-specific E2F target genes and cell death consistently occurred in the S phase of the cell cycle. Cell cycle arrest induced by serum starvation prevented S phase entry, attenuated DNA damage, and promoted survival, suggesting that Rb-null cells die due to a failure to prevent S phase entry. DNA damage-induced death of Rb-null cells was associated with nucleotide depletion, higher activity of poly-ADP-ribose-polymerase (Parp), and cell death that was primarily necrotic. Knockdown of Parp-1 or chemical inhibition of Parp activity prevented nucleotide depletion and restored the viability of Rb-deficient cells to wild-type levels. Furthermore, chemical inhibition of Parp activity in vivo attenuated the cytotoxic effects of cisplatin against Rb-deficient tumors, arguing that Parp inhibitors should not be used therapeutically in combination with genotoxic drugs against tumors that are inactivated for the Rb tumor suppressor.
Liu
Huiping
H
The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, Illinois 60637, USA.
Knabb
James R
JR
Spike
Benjamin T
BT
Macleod
Kay F
KF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016161:Genes, Retinoblastoma; D006801:Humans; D051379:Mice; D009243:NAD / Q000378:metabolism; D009336:Necrosis; D009711:Nucleotides / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011419:Propidium / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000172:deficiency*
D009711:Nucleotides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016160:Retinoblastoma Protein; D009243:NAD; D011419:Propidium; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin