Format

Send to:

Choose Destination
See comment in PubMed Commons below
Mol Cancer Res. 2009 Jul;7(7):1099-109. doi: 10.1158/1541-7786.MCR-08-0439. Epub 2009 Jul 7.

Elevated poly-(ADP-ribose)-polymerase activity sensitizes retinoblastoma-deficient cells to DNA damage-induced necrosis.

Author information

  • 1The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, Illinois 60637, USA.

Abstract

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.

PMID:
19584263
[PubMed - indexed for MEDLINE]
PMCID:
PMC2994938
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk