NNK, a tobacco-specific carcinogen, inhibits the expression of lysyl oxidase, a tumor suppressor.
NNK, a tobacco-specific carcinogen, inhibits the expression of lysyl oxidase, a tumor suppressor.
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DOI：
10.3390/ijerph120100064
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发表时间：
2014-12-23
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Cheng G;Li J;Zheng M;Zhao Y;Zhou J;Li W
烟草特有的致癌物质4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone被认为是导致吸烟者癌症负担的原因。为了评价NNK对肿瘤抑制因子赖氨酰氧化酶(LOX)表达的影响，我们在不同水平检测了NNK处理的大鼠胎肺成纤维细胞(RFL6)中赖氨酰氧化酶(LOX)的表达。细胞暴露于NNK可降低稳态LOX mRNA水平和新的转录合成。NNK对所有LOX蛋白的抑制作用呈剂量依赖关系。尽管300µM NNK显著降低了46 kDa前酶原的水平，但在相同的条件下，没有检测到50 kDa前酶原和32 kDa成熟酶，这表明NNK干扰了LOX蛋白的成熟加工。此外，NNK还抑制处理细胞条件培养液中的LOX活性。在启动子水平上，NNK促进了LOX基因核心启动子区域CpG的甲基化，但降低了组蛋白H3的乙酰化。这些结果表明LOX的转录和翻译过程是NNK的主要靶点。因此，抑癌基因LOX的失活可能在NNK的癌变过程中起关键作用。
A tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is believed to contribute to the cancer burden in cigarette smokers. To evaluate NNK effects on the expression of lysyl oxidase (LOX), a tumor suppressor, we examined this enzyme at various levels in NNK-treated rat fetal lung fibroblasts (RFL6). Exposure of cells to NNK reduced levels of steady-states LOX mRNA and new transcript synthesis. NNK inhibited all LOX protein species in a dose-dependent manner. Although 300 µM NNK markedly decreased the level in the 46 kDa preproenzyme, under same conditions, there was no detectable amounts of the 50 kDa proenzyme and the 32 kDa mature enzyme suggesting NNK perturbing the LOX protein processing to its mature form. Moreover, NNK also suppressed LOX activities in conditioned media of treated cells. At the promoter level, NNK enhanced methylation of CpG, but decreased acetylation of histone H3 at the core promoter region of the LOX gene. These results indicated that transcriptional and translational processes of LOX are major targets for NNK. Thus, inactivation of tumor suppressor gene LOX may play a critical role in NNK carcinogenesis.
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