Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane.
Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane.
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DOI：
10.1016/j.taap.2018.06.003
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发表时间：
2018-08-15
影响因子：
3.8
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Wang Y;Mandal AK;Son YO;Pratheeshkumar P;Wise JTF;Wang L;Zhang Z;Shi X;Chen Z
环境和职业接触镉会增加患各种癌症的风险，包括肺癌。镉的致癌机制及其预防仍有待研究。利用荧光和电子自旋共振自旋捕获技术，本研究表明，在永生化肺细胞（BEAS-2BR细胞），暴露镉产生活性氧（ROS）。镉通过ROS的产生增加了TNF-α的蛋白水平，从而激活了NF-κB及其靶蛋白考克斯-2，创造了炎症微环境。通过锚定非依赖性集落形成试验测定，镉诱导恶性细胞转化。通过抗氧化剂抑制ROS抑制转化，表明ROS在该过程的机制中是重要的。镉所产生的炎症微环境也可能有助于转化的机制。利用串联荧光蛋白mCherry-GFP-LC 3构建体，本研究表明镉转化细胞具有自噬缺陷的性质，导致自噬体的积累和p62的增加。该蛋白上调Nrf 2，Nrf 2也通过正反馈机制上调p62。组成性Nrf 2激活增加了其下游抗凋亡蛋白Bcl-2和Bcl-xl，导致凋亡抗性。在未转化的BEAS-2BR细胞中，萝卜硫素，一种天然化合物，增加自噬，激活Nrf 2，并减少ROS。在镉转化的BEAS-2BR细胞中，萝卜硫素恢复自噬，减少Nrf 2，并降低凋亡抵抗。在未转化的细胞中，这种萝卜硫素诱导诱导型Nrf 2减少ROS和可能的恶性细胞转化。在镉转化的细胞中，它减少了组成型Nrf 2，降低了凋亡抗性。萝卜硫素的双重作用使这种天然化合物成为预防镉诱导的致癌作用的有价值的试剂。
Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remain to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α, which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment. As measured by anchorage-independent colony formation assay, cadmium induced malignant cell transformation. Inhibition of ROS by antioxidants inhibited transformation, showing that ROS were important in the mechanism of this process. The inflammatory microenvironment created by cadmium may also contribute to the mechanism of the transformation. Using tandem fluorescence protein mCherry-GFP-LC3 construct, the present study shows that cadmium-transformed cells had a property of autophagy deficiency, resulting in accumulation of autophagosomes and increased p62. This protein upregulated Nrf2, which also upregulated p62 through positive feed-back mechanism. Constitutive Nrf2 activation increased its downstream anti-apoptotic proteins, Bcl-2 and Bcl-xl, resulting in apoptosis resistance. In untransformed BEAS-2BR cells, sulforaphane, a natural compound, increased autophagy, activated Nrf2, and decreased ROS. In cadmium-transformed BEAS-2BR cells, sulforaphane restored autophagy, decreased Nrf2, and decreased apoptosis resistance. In untransformed cells, this sulforaphane induced inducible Nrf2 to decrease ROS and possibly malignant cell transformation. In cadmium-transformed cells, it decreased constitutive Nrf2 and reduced apoptosis resistance. The dual roles of sulforaphane make this natural compound a valuable agent for prevention against cadmium-induced carcinogenesis.
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影响因子：
6.7
作者：
Brandenburg, Lars-Ove;Kipp, Markus;Wruck, Christoph J.
通讯作者：
Wruck, Christoph J.
影响因子：
2.9
作者：
KE, Y;REDDEL, RR;HARRIS, CC
通讯作者：
HARRIS, CC
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J
DOI：
10.1093/jnci/90.6.455
发表时间：
1998-03-18
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Hwang, D;Scollard, D;Levine, E
通讯作者：
Levine, E
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje