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

Journal article

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.

Authors: Papadakis, E; Cichoń, M; Vyas, J; Patel, N; Ghali, L

• Publication status: Published
• Journal: Journal of investigative dermatology
• Volume: 131
• Issue: 2
• Pages: 509-517
• Publication date: 2011-02-01
• DOI: 10.1038/jid.2010.326
• EISSN: 1523-1747
• ISSN: 0022-202X
• Language: English
• Keywords: Cell Survival; Skin Neoplasms; Cytochromes c; Humans; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; bcl-2 Homologous Antagonist-Killer Protein; Cell Line, Tumor; bcl-Associated Death Protein; Ultraviolet Rays; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; bcl-2-Associated X Protein; Carcinoma, Squamous Cell; Proto-Oncogene Proteins; Cell Proliferation; Apoptosis; Signal Transduction