Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Oncogene. 2013 Jul 4;32(27):3254-62. doi: 10.1038/onc.2012.338. Epub 2012 Aug 13.
Epidermal squamous cell carcinoma (SCC) is the most aggressive non-melanoma skin cancer and is dramatically increased in patients undergoing immunosuppression following solid organ transplantation, contributing substantially to morbidity and mortality. Recent clinical studies show that use of the mammalian target of rapamycin (mTOR) inhibitor rapamycin as a post-transplantation immunosuppressive significantly reduces SCC occurrence compared with other immunosuppressives, though the mechanism is not fully understood. We show that rapamycin selectively upregulates epidermal Akt1, while failing to upregulate epidermal Akt2. Rapamycin increases epidermal Akt1 phosphorylation via inhibition of the mTOR complex 1-dependent regulation of insulin receptor substrate-1. Epidermal Akt1 is commonly downregulated in SCC while Akt2 is upregulated. We now demonstrate similar Akt1 downregulation and Akt2 upregulation by ultraviolet (UV) radiation, the most important skin carcinogen. Hence, rapamycin's upregulation of Akt1 signaling could potentially oppose the effects of UV radiation and/or tumor-associated changes on Akt1 signaling. We show in skin culture that rapamycin does enhance restoration of Akt1 phosphorylation in skin recovering from UV radiation, suggesting a mechanism for rapamycin's antitumor activity in epidermis in spite of its efficient immunosuppressive properties.
表皮鳞状细胞癌（SCC）是最具侵袭性的非黑色素瘤皮肤癌，在实体器官移植后接受免疫抑制的患者中显著增加，大大增加了发病率和死亡率。最近的临床研究表明，使用哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂雷帕霉素作为移植后的免疫抑制剂，与其他免疫抑制剂相比，显著降低 SCC 的发生，尽管其机制尚未完全阐明。我们发现雷帕霉素选择性地上调表皮 Akt1，而不能上调表皮 Akt2。雷帕霉素通过抑制 mTOR 复合物 1 对胰岛素受体底物-1 的调节，增加表皮 Akt1 的磷酸化。表皮 Akt1 在 SCC 中通常下调，而 Akt2 上调。我们现在证明，紫外线（UV）辐射这一最重要的皮肤致癌剂，也具有类似的 Akt1 下调和 Akt2 上调作用。因此，雷帕霉素对 Akt1 信号的上调可能会抵消 UV 辐射和/或肿瘤相关变化对 Akt1 信号的影响。我们在皮肤培养中表明，雷帕霉素确实增强了从 UV 辐射中恢复的皮肤中 Akt1 磷酸化的恢复，这表明尽管雷帕霉素具有有效的免疫抑制特性，但它在表皮中的抗肿瘤活性具有一种机制。
