Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans.
Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans.
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DOI：
10.1158/1940-6207.capr-14-0362
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发表时间：
2015-06
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影响因子：
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通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
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作者：
Knatko EV;Ibbotson SH;Zhang Y;Higgins M;Fahey JW;Talalay P;Dawe RS;Ferguson J;Huang JT;Clarke R;Zheng S;Saito A;Kalra S;Benedict AL;Honda T;Proby CM;Dinkova-Kostova AT
转录因子Nrf 2通过调节包含近500个编码具有多功能细胞保护功能的蛋白质的基因的精细网络的表达来确定在亲电、氧化和炎症应激条件下的适应和存活能力。在小鼠中，Nrf 2的破坏增加了对致癌物的易感性并加速了疾病的发病机制。奇怪的是，Nrf 2在已建立的人类肿瘤中上调，但这种上调是否驱动致癌尚不清楚。在这里，我们表明，在SKH-1无毛小鼠中形成的太阳模拟紫外线辐射介导的皮肤肿瘤的发病率，多样性和负担，其中Nrf 2基因组成型激活，低于野生型对应物中出现的。在接受免疫抑制剂硫唑嘌呤长期治疗的动物中，每两周局部应用少量（40 nmol）强效双（氰基烯酮）诱导剂TBE-31进行药理学Nrf 2激活，对模拟太阳紫外线辐射具有类似的保护作用。在小鼠急性暴露于UV辐射后，遗传或药理学Nrf 2激活降低促炎因子白细胞介素（IL）-6和IL-1β以及环氧合酶（考克斯）-2的表达。在健康的人类受试者中，局部施用递送Nrf 2活化剂萝卜硫素的提取物，降低了太阳模拟紫外线辐射诱导的皮肤红斑的程度，这是皮肤损伤和皮肤癌风险的可量化的替代终点。总的来说，这些数据表明，即使暴露于非常有效和完全的致癌物，Nrf 2也不是肿瘤发生的驱动因素，并强烈表明，在已建立的人类肿瘤中，Nrf 2的频繁激活是代谢适应的标志。
The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated, are lower than those that arise in their wild-type counterparts. Pharmacological Nrf2 activation by topical bi-weekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacological Nrf2 activation lowers the expression of the pro-inflammatory factors interleukin (IL)-6 and IL-1β, and cyclooxygenase (COX)-2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane, reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate end-point for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen, and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation.