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Modulation of p53 transcriptional activity by PRIMA-1 and Pifithrin-α on staurosporine-induced apoptosis of wild-type and mutated p53 epithelial cells

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Abstract

We recently argued for a major role of p53 in staurosporine(ST)-induced apoptosis of immortalized epithelial cells, depending on their p53 status. Here, we studied the effects of PRIMA-1 (p53 reactivation and induction of massive apoptosis) and Pifithrin-α (p fifty-three inhibitor) in combination with ST to reinforce our previous results by respectively restoring or inhibiting the p53 transcriptional activity in different cell lines.

PRIMA-1 does modify neither expression of apoptosis-related proteins nor the percentage of wild-type p53 HeLa and CaSki cells with ➘ΔΨm and DNA cleavage, whilst it increases by 45% Bax expression and apoptosis of mutated p53 C33A cells. Pifithrin-α, does modify neither Bax expression nor apoptosis level of C33A cells, but readily inhibits both ➘ΔΨm and DNA fragmentation of p53wt cells with decreasing Bax expression. These data support the evidence that PRIMA-1 could be a good candidate, as an anti-cancer drug targeting mutant p53, in order to increase ST efficiency. Moreover, Pifithrin-α could be used in combination with ST and PRIMA-1 to prevent side effects of anti-tumor therapies in cells expressing mutant P53.

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Abbreviations

ST:

staurosporine

PFT-α:

pifithrin-α

ΔΨm :

mitochondrial membrane potential

ΔΨm :

mitochondrial membrane depolarization

PBS:

phosphate-buffered saline

wt:

wild-type

mt:

mutated

DBD:

DNA binding domain

HPV:

human papillomavirus

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Authors and Affiliations

  1. Université de Franche-Comté, UFR Médecine et Pharmacie, EA 3181, IFR 133. 19 rue Ambroise Paré, 25000, Besançon, France

    J. F. Charlot, M. Nicolier, J. L. Prétet & C. Mougin

  2. Laboratoire de Biologie Cellulaire et Moléculaire, CHU Jean Minjoz, 2 Boulevard, Fleming, Besançon Cedex, 25030, France

    C. Mougin

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  1. J. F. Charlot
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  2. M. Nicolier
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  3. J. L. Prétet
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  4. C. Mougin
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Correspondence to C. Mougin.

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Charlot, J.F., Nicolier, M., Prétet, J.L. et al. Modulation of p53 transcriptional activity by PRIMA-1 and Pifithrin-α on staurosporine-induced apoptosis of wild-type and mutated p53 epithelial cells. Apoptosis 11, 813–827 (2006). https://doi.org/10.1007/s10495-006-5876-6

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