Effect of poly(ADP-ribose)polymerase and DNA topoisomerase I inhibitors on the p53/p63-dependent survival of carcinoma cells.

Abstract

Depending on their genetic background (p53(wt) versus p53(null)), carcinoma cells are more or less sensitive to drug-induced cell cycle arrest and/or apoptosis. Among the members of the p53 family, p63 is characterized by two N-terminal isoforms, TAp63 and ΔNp63. TAp63 isoform has p53-like functions, while ΔNp63 acts as a dominant negative inhibitor of p53. We have previously published that TAp63 is involved in poly(ADP-ribose)polymerase-1 (PARP-1) signaling of DNA damage deriving from DNA topoisomerase I (TOP I) inhibition in carcinoma cells. In the present study, we treated MCF7 breast carcinoma cells (p53(+)/ΔNp63(-)) or SCC022 (p53(-)/ΔNp63(+)) squamous carcinoma cells with the TOP I inhibitor topotecan (TPT) and the PJ34 PARP inhibitor, to compare their effects in the two different cell contexts. In MCF7 cells, we found that PJ34 addition reverts TPT-dependent PARP-1 auto-modification and triggers caspase-dependent PARP-1 proteolysis. Moreover, TPT as single agent stimulates p53(ser15) phosphorylation, p53 PARylation and occupancy of the p21WAF promoter by p53 resulting in an increase of p21WAF expression. Interestingly, PJ34 in combination with TPT enhances p53 occupancy at the BAX promoter and is associated with increased BAX protein level. In SCC022 cells, instead, TPT+PJ34 combined treatment reduces the level of the anti-apoptotic ΔNp63α protein without inducing apoptosis. Remarkably, in such cells, either exogenous p53 or TAp63 can rescue the apoptotic program in response to the treatment. All together our results suggest that in cancer cells PARP inhibitor(s) can operate in the choice between growth arrest and apoptosis by modulating p53 family-dependent signal.

• Authors: Daniela Montariello, Annaelena Troiano, Daniela Di Girolamo, Sascha Beneke, Viola Calabrò, Piera Quesada
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 94 Issue 3 Pg. 212-9 (Apr 01 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 25667043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• CKAP4 protein, human
• DNA Primers
• Membrane Proteins
• Topoisomerase I Inhibitors
• Tumor Suppressor Protein p53
• Poly(ADP-ribose) Polymerases

Topics

• Base Sequence
• Cell Survival (drug effects, physiology)
• DNA Primers
• Humans
• MCF-7 Cells
• Membrane Proteins (physiology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Processing, Post-Translational
• Real-Time Polymerase Chain Reaction
• Topoisomerase I Inhibitors (pharmacology)
• Tumor Suppressor Protein p53 (physiology)