xCT deficiency accelerates chemically induced tumorigenesis
xCT deficiency accelerates chemically induced tumorigenesis
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DOI：
10.1073/pnas.0912827107
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发表时间：
2010-04-06
影响因子：
11.1
通讯作者：
Tanaka, Masato
中科院分区：
文献类型：
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作者：
Nabeyama, Ami;Kurita, Ai;Tanaka, Masato
在炎症及其消退过程中，巨噬细胞暴露于各种细胞毒性物质，包括活性氧。因此，巨噬细胞需要一种抗氧化应激的保护机制才能在炎症部位存活。在这里，我们发现xCT，运输系统x(c)（-）的一个组成部分，在激活的浸润细胞中显著上调，包括炎症部位的巨噬细胞和中性粒细胞。系统x(c)（-）介导细胞外l -胱氨酸的摄取，因此负责维持细胞内谷胱甘肽水平。我们通过n -乙基-n -亚硝基脲诱变建立了xCT小鼠功能缺失突变系。LPS刺激下，xCT（mu/mu）小鼠巨噬细胞出现细胞死亡与高迁移率组盒染色体蛋白1的过量释放有关，提示xCT缺乏导致炎症部位活化巨噬细胞存活受损，从而导致持续炎症。皮下注射3-甲基胆蒽（3-MCA）诱导与炎症相关的纤维肉瘤的产生。将3-MCA注射到小鼠体内后，xCT mRNA原位表达上调。在xCT（mu/mu）小鼠中，炎性细胞因子（如IL-1 β和TNF α）过表达，3- mca诱导的纤维肉瘤生成加快。这些结果清楚地表明，氧化应激保护系统的缺陷损害了活化巨噬细胞的存活，随后增强了致瘤性。
During the course of inflammation and its resolution, macrophages are exposed to various cytotoxic materials, including reactive oxygen species. Thus, macrophages require a protective machinery against oxidative stress to survive at the inflammatory site. Here, we showed that xCT, a component of transport system x(c)(-), was significantly up-regulated in activated infiltrating cells, including macrophages and neutrophils at the inflammatory site. System x(c)(-) mediates the uptake of extracellular L-cystine and is consequently responsible for maintenance of intracellular glutathione levels. We established a loss-of-function mouse mutant line of xCT by N-ethyl-N-nitrosourea mutagenesis. Macrophages from xCT(mu/mu) mice showed cell death in association with the excessive release of high mobility group box chromosomal protein 1 upon stimulation with LPS, suggesting that xCT deficiency causes unremitting inflammation because of the impaired survival of activated macrophages at the inflammatory site. Subcutaneous injection of 3-methylcholanthrene (3-MCA) induced the generation of fibrosarcoma in association with inflammation. When 3-MCA was injected s.c. into mice, xCT mRNA was up-regulated in situ. In xCT(mu/mu) mice, inflammatory cytokines (such as IL-1 beta and TNF alpha) were overexpressed, and the generation of 3-MCA-induced fibrosarcoma was accelerated. These results clearly indicate that the defect of the protective system against oxidative stress impaired survival of activated macrophages and subsequently enhanced tumorigenecity.