Rahman Hafeez, Liu Tong, Askaryar Sajjad, Grossman Douglas
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
University of Utah School of Medicine, Salt Lake City, Utah, USA.
J Invest Dermatol. 2023 Jan;143(1):154-162.e3. doi: 10.1016/j.jid.2022.07.011. Epub 2022 Aug 2.
The anti-inflammatory and chemopreventive activities of aspirin (ASA) may be mediated through its cyclooxygenase inhibitor function. We have previously shown that ASA can protect against UVR-induced skin inflammation and DNA damage; however, the role of inflammation in UV-induced DNA damage and the mechanism underlying ASA protection are poorly characterized. Using immunodeficient NOD scid gamma mice and immunocompetent C57BL/6 mice treated with immune cell‒depleting antibodies, we found that inflammation was not required for UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in vivo. Unlike ASA, neither its immediate metabolite salicylate nor the cyclooxygenase inhibitor indomethacin reduced UVB-induced 8-oxoguanine or cyclobutane pyrimidine dimers in melanocyte Melan-a or keratinocyte HaCat cells in vitro. Moreover, addition of prostaglandin E did not reverse the protective effect of ASA on UVB-treated cells. Phosphorylation of the 5' AMP protein kinase, observed in ASA-treated cells, could be blocked by the 5' AMP protein kinase inhibitor compound C. Compound C or 5' AMP protein kinase knockdown partially reduced ASA-mediated protection against UVB-induced DNA damage. Finally, injection of compound C partially reversed the protective effect of ASA on UVB-treated mouse skin in vivo. These studies suggest that ASA confers protection against UVB-induced DNA damage through the activation of 5' AMP protein kinase rather than through cyclooxygenase inhibition.
阿司匹林（ASA）的抗炎和化学预防活性可能是通过其环氧化酶抑制功能介导的。我们之前已经表明，ASA可以预防紫外线辐射（UVR）诱导的皮肤炎症和DNA损伤；然而，炎症在紫外线诱导的DNA损伤中的作用以及ASA保护作用的潜在机制仍不清楚。使用免疫缺陷的NOD scid gamma小鼠和用免疫细胞耗竭抗体处理的免疫活性C57BL/6小鼠，我们发现在体内，紫外线B（UVB）诱导的8-氧代鸟嘌呤和环丁烷嘧啶二聚体并不需要炎症。与ASA不同，其直接代谢产物水杨酸酯和环氧化酶抑制剂吲哚美辛在体外均未降低黑素细胞Melan-a或角质形成细胞HaCat细胞中UVB诱导的8-氧代鸟嘌呤或环丁烷嘧啶二聚体。此外，添加前列腺素E并不能逆转ASA对UVB处理细胞的保护作用。在ASA处理的细胞中观察到的5'-AMP蛋白激酶的磷酸化可被5'-AMP蛋白激酶抑制剂化合物C阻断。化合物C或5'-AMP蛋白激酶敲低部分降低了ASA介导的对UVB诱导的DNA损伤的保护作用。最后，注射化合物C部分逆转了ASA对体内UVB处理的小鼠皮肤的保护作用。这些研究表明，ASA通过激活5'-AMP蛋白激酶而不是通过抑制环氧化酶来赋予对UVB诱导的DNA损伤的保护作用。
