Kopnin Pavel B, Kravchenko Irina V, Furalyov Vladimir A, Pylev Lev N, Kopnin Boris P
Institute of Carcinogenesis, Blokhin Cancer Research Center, Kashirskoye shosse 24, Moscow 115478, Russia.
Oncogene. 2004 Nov 18;23(54):8834-40. doi: 10.1038/sj.onc.1208108.
Exposure to asbestos fibers increases the risk of development of mesotheliomas and lung carcinomas, but not fibrosarcomas. We present data suggesting that resistance of fibroblasts to asbestos-induced carcinogenesis is likely to be connected with their lower ability to generate reactive oxygen species (ROS) in response to asbestos exposure and stricter control of proliferation of cells bearing asbestos/ROS-induced injuries. In fact, chrysotile (Mg6Si4O10(OH)8) asbestos exposure (5-10 microg/cm2) increased intracellular ROS and 8-oxo-guanine contents in rat pleural mesothelial cells, but not in lung fibroblasts. Simultaneously, moderate dosages of chrysotile and other agents increasing ROS levels (hydrogen peroxide, H2O2 and ethyl-methanesulfonate, EMS) inhibited cell cycle progression, in particular G1-to-S transition, in fibroblasts, but not in mesothelial cells. The arrested fibroblasts underwent cell death, while the majority of chrysotile-treated mesothelial cells survived. The differences in cell cycle response to asbestos/ROS-induced injuries correlated with distinct activity of p53-p21Cip1/Waf1 pathway in the two cell types. Chrysotile, H2O2 and EMS caused p53 upregulation in both cell types, but mesothelial cells, unlike fibroblasts, showed no accumulation of p21Cip1/Waf1. Of note, treatment with doxorubicin caused similar p53-dependent p21Cip1/Waf1 upregulation and cell cycle arrest in both cell types. This suggests differential response of fibroblasts and mesothelial cells specifically to asbestos/ROS exposure rather than to all DNA-damaging insults.
接触石棉纤维会增加患间皮瘤和肺癌的风险，但不会增加患纤维肉瘤的风险。我们提供的数据表明，成纤维细胞对石棉诱导的致癌作用的抗性可能与其在接触石棉时产生活性氧（ROS）的能力较低以及对承受石棉/ROS诱导损伤的细胞增殖的更严格控制有关。事实上，温石棉（Mg6Si4O10(OH)8）暴露（5-10微克/平方厘米）会增加大鼠胸膜间皮细胞内的ROS和8-氧代鸟嘌呤含量，但不会增加肺成纤维细胞内的含量。同时，中等剂量的温石棉和其他增加ROS水平的试剂（过氧化氢、H2O2和甲基磺酸乙酯、EMS）会抑制成纤维细胞的细胞周期进程，特别是G1期到S期的转换，但不会抑制间皮细胞的细胞周期进程。停滞的成纤维细胞会发生细胞死亡，而大多数经温石棉处理的间皮细胞存活下来。两种细胞类型对石棉/ROS诱导损伤的细胞周期反应差异与p53-p21Cip1/Waf1通路在两种细胞类型中的不同活性相关。温石棉、H2O2和EMS在两种细胞类型中均导致p53上调，但与成纤维细胞不同，间皮细胞未显示p21Cip1/Waf1的积累。值得注意的是，阿霉素处理在两种细胞类型中均导致类似的p53依赖性p21Cip1/Waf1上调和细胞周期停滞。这表明成纤维细胞和间皮细胞对石棉/ROS暴露而非所有DNA损伤性刺激具有不同的反应。
