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

来源：

CANCER LETTERS | 2009年 / 276卷 / 02期

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

页码：143 / 151

页数：9

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