Nordihydroguaiaretic acid-mediated inhibition of ultraviolet B-induced activator protein-1 activation in human keratinocytes
Nordihydroguaiaretic acid-mediated inhibition of ultraviolet B-induced activator protein-1 activation in human keratinocytes
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DOI：
10.1002/mc.10052
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发表时间：
2002-06-01
影响因子：
4.6
通讯作者：
Bowden, GT
中科院分区：
文献类型：
--
作者：
Gonzales, M;Bowden, GT
去甲二氢愈创木酸（NDGA）是一种多酚类化合物，从Larrea tridentata布什已被确定为一种化学预防药物在动物研究。局部应用的NDGA已被证明可以防止佛波醇酯促进小鼠皮肤中的肿瘤，这表明NDGA可能是皮肤癌化学预防的候选药物。紫外线（UV）B辐射是人类皮肤癌的主要原因。UVB照射引起靶角质形成细胞的表观遗传改变，例如诱导转录因子表达的信号转导途径的上调。具体来说，UVB诱导激活蛋白-1（AP-1），一种改变正常细胞基因表达的转录因子复合物。UVB诱导的AP-1复合物的一个组分c-fos也被鉴定为导致AP-1活化的信号通路的介质。因此，NDGA作为一种潜在的抑制剂UVB诱导的信号转导途径在人类角质形成细胞系HaCaT的研究。NDGA显著抑制UVB诱导的c-fos和AP-1转录激活。此外，NDGA被发现抑制磷脂酰肌醇3-激酶（PI 3-激酶），UVB诱导的酶，有助于诱导表达的c-fos和AP-1的活性。因此，NDGA通过抑制PI 3-激酶信号通路阻止UVB诱导的c-fos表达和AP-1反式激活。有效的皮肤化学预防策略可能会纳入NDGA抑制UVB诱导的细胞信号通路，增加AP-1活性的组件。(C)2002 Wiley-Liss，Inc.
Nordihydroguaiaretic acid (NDGA) is a polyphenolic compound from the Larrea tridentata bush that has been identified as a chemopreventive drug in animal studies. Topically applied NDGA has been shown to prevent phorbol ester promotion of tumors in mouse skin, suggesting that NDGA may be a candidate drug for the chemoprevention of skin cancer. Ultraviolet (UV) B irradiation from sunlight exposure is the major cause of human skin cancer. UVB irradiation causes epigenetic alterations in target keratinocytes, such as the upregulation of signal transduction pathways that induce the expression of transcription factors. Specifically, UVB induces activator protein-1 (AP-1), a transcription factor complex that alters normal cellular gene expression. A component of the UVB-induced AP-1 complex, c-fos, also was identified as a mediator of the signaling pathway that leads to AP-1 activation. Thus, NDGA was investigated as a potential inhibitory agent for UVB-induced signaling pathways in the human keratinocyte cell line HaCaT. NDGA significantly inhibited UVB-induced c-fos and AP-1 transactivation. In addition, NDGA was found to inhibit activity of phosphatidylinositol 3-kinase (PI 3-kinase), a UVB-inducible enzyme that contributes to the induced expression of c-fos and AP-1. Therefore, NDGA prevents UVB-induced c-fos expression and AP-1 transactivation by inhibiting the PI 3-kinase signaling pathway. Effective skin chemoprevention strategies may incorporate NDGA to inhibit components of the UVB-induced cell signaling pathways that increase AP-1 activity. (C) 2002 Wiley-Liss, Inc.