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Molecular determinants of Akt-induced keratinocyte transformation

Oncogene volume 25, pages 1174–1185 (2006)Cite this article

Abstract

The PI3K/PTEN/Akt signaling pathway has emerged in recent years as a main player in human cancers, increasing proliferation and decreasing apoptosis of transformed cells, and thus becoming a potential target for therapeutic intervention. Our previous data have demonstrated that Akt-mediated signaling is of a key relevance in the mouse skin carcinogenesis system, one of the best-known models of experimental carcinogenesis. Here, we investigated the involvement of several pathways as mediators of Akt-induced increased proliferation and tumorigenesis in keratinocytes. Tumors produced by subcutaneous injection of Akt-transformed keratinocytes showed increased Foxo3a phosphorylation, but no major alterations in p21Cip1/WAF1, p27Kip1 or mdm2 expression and/or localization. In contrast, we found increased expression and nuclear localization of ΔNp63, β-catenin and Lef1. Concomitantly, we also found increased expression of c-myc and CycD1, targets of the β-catenin/Tcf pathway. Such increase is associated with increased phosphorylation and stabilization of c-myc protein as well as increased translation of c-myc and CycD1 due to mTOR activation. Using immunohistochemistry approaches in samples of oral dysplasias and human head and neck squamous cell carcinomas, we confirmed that increased Akt activation significantly correlates with increased ΔNp63 and CycD expression, c-myc phosphorylation and nuclear accumulation of β-catenin. Collectively, these results demonstrate that Akt is able to transform keratinocytes by specific mechanisms involving transcriptional and post-transcriptional processes.

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Abbreviations

SCC:

squamous cell carcinoma

TPA:

12-O-tetradecanoyl-phorbol- 13-acetate

DMBA:

7, 12-dimethyl-benz(a)anthracene

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Acknowledgements

We thank S Gutkind for providing materials, the animal facility personnel of the CIEMAT for the excellent care of the animals and the Histology facility for their work involving the histological preparations. This work was partially supported by Grant SAF2002-01037 from the CICYT, La Caixa Foundation and GR/SAL/0103/2004 from CAM.

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Author notes

  1. S Ruiz

    Present address: Cancer Research Center and Institute of Cell and Molecular Biology of Cancer, CSIC-University of Salamanca, P Universidad de Coimbra s/n, Salamanca, Spain

  2. H Leis

    Present address: Genomics and Pharmacoproteomics Program, FVIB-CIPF, Camino de las Moreras, Valencia, Spain

  3. C Segrelles and M Moral: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Molecular Biology, CIEMAT, Madrid, Spain

    C Segrelles, M Moral, M Fernanda Lara, S Ruiz, M Santos, H Leis, R García-Escudero, A B Martínez-Cruz, J Martínez-Palacio, P Hernández & J M Paramio

  2. Department of Pathology, Hospital ‘12 de Octubre’, Madrid, Spain

    C Ballestín

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Correspondence to J M Paramio.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Segrelles, C., Moral, M., Lara, M. et al. Molecular determinants of Akt-induced keratinocyte transformation. Oncogene 25, 1174–1185 (2006). https://doi.org/10.1038/sj.onc.1209155

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