Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1.
Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1.
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DOI：
10.1158/0008-5472.can-08-4841
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Gladson CL
中科院分区：
文献类型：
--
作者：
McFarland BC;Stewart J Jr;Hamza A;Nordal R;Davidson DJ;Henkin J;Gladson CL
Recombinant plasminogen kringle 5 (rK5) has been shown to induce apoptosis of dermal microvessel endothelial cells (MvEC) in a manner that requires glucose-regulated protein 78 (GRP78). As we are interested in anti-angiogenic therapy for glioblastoma tumors, and the effectiveness of anti-angiogenic therapy can be enhanced when combined with radiation, we investigated the pro-apoptotic effects of rK5 combined with radiation on brain MvEC. We found that rK5 treatment of brain MvEC induced apoptosis in a dose- and time-dependent manner, and that prior irradiation significantly sensitized (500-fold) the cells to rK5-induced apoptosis. The rK5-induced apoptosis of both unirradiated and irradiated MvEC required expression of GRP78 and the low density lipoprotein receptor-related protein 1 (LRP1), a scavenger receptor, based on downregulation studies with small interfering RNA, and blocking studies with either a GRP78 antibody or a competitive inhibitor of ligand binding to LRP1. Furthermore, p38 MAP kinase was found to be a necessary downstream effector for rK5-induced apoptosis. These data suggest that irradiation sensitizes brain MvEC to the rK5-induced apoptosis and that this signal requires LRP1 internalization of GRP78 and the activation of p38 MAP kinase. Our findings suggest that prior irradiation would have a dose-sparing effect on rK5 anti-angiogenic therapy for brain tumors and further suggest that the effects of rK5 would be tumor-specific as the expression of GRP78 protein is upregulated on the brain MvEC in glioblastoma tumor biopsies as compared to the normal brain.
