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Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development

Oncogene volume 24, pages 7012–7021 (2005)Cite this article

Abstract

ped/pea-15 is a cytosolic protein performing a broad antiapoptotic function. We show that, upon DMBA/TPA-induced skin carcinogenesis, transgenic mice overexpressing ped/pea-15 (Tgped/pea-15) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (P<0.001). The malignant conversion frequency was 24% for the Tgped/pea-15 mice and only 5% in controls (P<0.01). The isolated application of TPA, but not that of DMBA, was sufficient to reversibly upregulate ped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tgped/pea-15 and control mice. Isolated TPA applications induced Caspase-3 activation and apoptosis in nontransformed mouse epidermal tissues. The induction of both Caspase-3 and apoptosis by TPA were four-fold inhibited in the skin of the Tgped/pea-15 compared to the nontransgenic mice, accompanied by a similarly sized reduction in TPA-induced JNK and p38 stimulation and by constitutive induction of cytoplasmic ERK activity in the transgenics. ped/pea-15 expression was stably increased in cell lines from DMBA/TPA-induced skin papillomas and carcinomas, paralleled by protection from TPA apoptosis. In the A5 spindle carcinoma cell line, antisense inhibition of ped/pea-15 expression simultaneously rescued sensitivity to TPA-induced Caspase-3 function and apoptosis. The antisense also reduced A5 cell ability to grow in semisolid media by 65% (P<0.001) and increased by three-fold tumor latency time (P<0.01). Thus, the expression levels of ped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development.

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Acknowledgements

We thank Dr A Balmain for kindly providing C5N, P1 and A5 cells and Dr S Linardopoulos for critical reading of the manuscript. The technical help of Maria Russo, Salvatore Sequino and Dr Antonio Baiano is also acknowledged. This work was supported by the European Community's FP6 EUGENE2 (LSHM-CT-2004-512013), grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to FB and PF, and the Ministero dell'Università e della Ricerca Scientifica (PRIN to FB, GiPo and PF and FIRB RBNE0155LB to FB). The financial support of Telethon – Italy is gratefully acknowledged.

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Via Sergio Pansini, 5, Naples, 80131, Italy

    Pietro Formisano, Giuseppe Perruolo, Silvana Libertini, Stefania Santopietro, Gregory Alexander Raciti, Francesco Oriente, Giuseppe Portella, Claudia Miele & Francesco Beguinot

  2. Dipartimento di Scienze Biomorfologiche e Funzionali of the Federico II University of Naples, Naples, Italy

    Giancarlo Troncone

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  1. Pietro Formisano
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  2. Giuseppe Perruolo
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  3. Silvana Libertini
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  4. Stefania Santopietro
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  5. Giancarlo Troncone
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  7. Francesco Oriente
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  8. Giuseppe Portella
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  9. Claudia Miele
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  10. Francesco Beguinot
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Correspondence to Francesco Beguinot.

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Formisano, P., Perruolo, G., Libertini, S. et al. Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. Oncogene 24, 7012–7021 (2005). https://doi.org/10.1038/sj.onc.1208871

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