Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
J Invest Dermatol. 2011 Feb;131(2):509-17. doi: 10.1038/jid.2010.326. Epub 2010 Nov 11.
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.
受体酪氨酸激酶 Axl 的表达在皮肤鳞状细胞癌（SCC）中增加。对一系列皮肤 SCC 肿瘤的检查显示，Axl 阳性肿瘤中存在磷酸化 Akt（P-Akt）染色阳性，而 TUNEL 染色较弱，这表明 Axl 在 SCC 存活中具有抗凋亡作用。我们使用逆转录病毒短发夹 RNA 序列研究了 Axl 在 UV 诱导的细胞凋亡中的作用，该序列可使 Axl 稳定敲低。我们表明，尽管 Axl 敲低对细胞增殖没有影响，但通过增加促凋亡蛋白 Bad 的激活、Bax 和 Bak 构象的改变、细胞色素 c 释放到细胞质中和 caspase 的激活，使细胞对 UV 诱导的凋亡敏感。这些事件伴随着 UV 处理的 Axl 敲低细胞中 Akt 去磷酸化的加速，并且与 Axl 敲低的程度相关。用泛半胱天冬酶抑制剂 zVAD-fmk 处理部分挽救了细胞免受 UV 诱导的凋亡，但不影响 Bid 切割或细胞色素 c 释放，表明细胞通过线粒体介导的途径死亡。因此，Axl 赋予 SCC 细胞对凋亡的抗性，并显示出作为皮肤 SCC 治疗干预的潜在靶点。
