p63 as a new player involved in the cancer cell response to chemotherapy

Poly (ADP-ribose)polymerase 1 (PARP-1) is involved in cellular processes such as DNA repair and apoptosis. Therefore, PARP-1 inhibitor (PJ34) is considered a potential treatment for p53 proficient breast and ovarian carcinoma cells, when combined with TOP I poisons. p63 is a member of the p53 family highly expressed in carcinoma cells of epithelial origin. In particular, TAp63 proteins mimic p53 transcriptional and proapoptotic functions whereas the ???Np63?? protein has been shown to repress p53-target genes acting as an oncogene. We have analyzed the sensitivity of MCF7 (p53wt), MDA-MB231 (p53mut ) breast carcinoma and SCC022 (p53null) squamous carcinoma cells to PJ34 and TOP I (CPT, TPT) inhibitors combined treatment. We show that MCF-7 cells exhibit apoptotic cell death while MDA-MB231 and SCC022 cells are resistant to these agents. In MCF7 cells PJ34 reverts TPT-dependent PARP-1 auto-modification and triggers caspase- dependent PARP-1 proteolysis. Furthermore, TPT as a single agent stimulates p53 expression while in combination with PJ34 also induces TAp63 proteins. In SCC022 cells we observed that degradation of endogenous ???Np63?? by TPT+PJ34 treatment is not sufficient to induce apoptosis thereby indicating that p53 and/or TAp63 is/are required to induce apoptosis. Our data suggest that p63 is a new player in the apoptosis pathway triggered by TOP I and PARP-1 inhibitors.