کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2511965 1118304 2015 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Effect of poly(ADP-ribose)polymerase and DNA topoisomerase I inhibitors on the p53/p63-dependent survival of carcinoma cells
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Effect of poly(ADP-ribose)polymerase and DNA topoisomerase I inhibitors on the p53/p63-dependent survival of carcinoma cells
چکیده انگلیسی

Depending on their genetic background (p53wt versus p53null), 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 p53ser15 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

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 94, Issue 3, 1 April 2015, Pages 212–219
نویسندگان
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