Axl promotes cutaneous squamous cell carcinoma survival through negative regulation of pro-apoptotic Bcl-2 family members

Papadakis, Emmanouil S. and Cichoń, Monika A. and Vyas, Jashmin J. and Patel, Nakul and Ghali, Lucy and Cerio, Rino and Storey, Alan and O'Toole, Edel A. (2011) Axl promotes cutaneous squamous cell carcinoma survival through negative regulation of pro-apoptotic Bcl-2 family members. Journal of Investigative Dermatology, 131 (2). pp. 509-517. ISSN 0022-202X

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Abstract

Expression of Axl, a receptor tyrosine kinase, is increased in cutaneous squamous cell carcinoma (SCC). Examination of a series of cutaneous SCC tumors revealed positive phospho-Akt (P-Akt) staining accompanied by weak TUNEL staining in Axl-positive tumors, suggesting an anti-apoptotic role for Axl in SCC survival. The role of Axl in UV-induced apoptosis was investigated in a cutaneous SCC cell line using retroviral short hairpin RNA sequences enabling stable Axl knock-down. We show that, although Axl knock-down has no effect on cell proliferation, it sensitizes cells to UV-induced apoptosis through increased activation of the pro-apoptotic protein Bad, a change in the conformation of Bax and Bak, release of cytochrome c into the cytosol, and activation of caspases. These events are accompanied by faster Akt dephosphorylation in UV-treated Axl knock-down cells and correlate with the degree of Axl knock-down. Treatment with the pan-caspase inhibitor zVAD-fmk partially rescued cells from UV-induced apoptosis but did not affect Bid cleavage or cytochrome c release, suggesting that cells die via the mitochondrial-mediated pathway. Thus, Axl confers resistance of SCC cells to apoptosis and displays potential as a target for therapeutic intervention in cutaneous SCC.

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
Item ID: 11113
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Depositing User: Devika Mohan
Date Deposited: 02 Jul 2013 06:24
Last Modified: 13 Oct 2016 14:27
URI: http://eprints.mdx.ac.uk/id/eprint/11113

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