p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway

被引:73
作者
Khromova, N. V. [1 ]
Kopnin, P. B. [2 ,3 ]
Stepanova, E. V. [1 ]
Agapova, L. S. [1 ]
Kopnin, B. P. [1 ]
机构
[1] Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
[2] VA Engelhardt Mol Biol Inst, Moscow 119991, Russia
[3] Univ Oslo, Ctr Med Studies Russia, Moscow 119334, Russia
基金
俄罗斯基础研究基金会;
关键词
p53; mutation; Tumor angiogenesis; ROS; HIF1; VEGF; ENDOTHELIAL GROWTH-FACTOR; INDUCIBLE FACTOR 1-ALPHA; WILD-TYPE P53; FACTOR EXPRESSION; SUPPRESSOR GENE; UP-REGULATION; IN-VIVO; ANGIOGENESIS; CELLS; INHIBITION;
D O I
10.1016/j.canlet.2008.10.049
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The function of p53 tumor suppressor is often altered in various human tumors predominantly through missense-mutations resulting in accumulation of mutant proteins. we revealed that expression of p53 proteins with amino-acid substitutions at codons 175 (R175H), 248 (R248W), and 273 (R273H), representing the hot-spots of mutations in various human tumors, increased the number of vessels in HCT116 human colon carcinoma xenografts and, as a result, accelerated their growth. Stimulation of tumor angiogenesis was connected with about 2-fold increase in intracellular level of reactive oxygen species (ROS). Antioxidant N-acetyl-L-aspartate (NAC) decreased vessels number in tumors formed by cells with inactivated p53 and inhibited their growth. Effect of ROS on angiogenesis in tumors expressing hot-spot p53 mutants was correlated with their ability to increase a content of HIF1 transcriptional factor responsible for up-regulation of VEGF-A mRNAs. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:143 / 151
页数:9
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