GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib
GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib
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DOI：
10.1182/blood-2009-03-209668
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发表时间：
2009-10-29
期刊：
影响因子：
20.3
通讯作者：
Steurer, Michael
中科院分区：
文献类型：
--
作者：
Kern, Johann;Untergasser, Gerold;Steurer, Michael
分析了蛋白酶体抑制剂硼替佐米对体内肿瘤异种移植物的抗血管生成作用。硼替佐米强烈抑制鸡绒毛尿囊膜中的血管生成和血管化。由于肿瘤细胞分泌的可溶性因子，硼替佐米对绒毛尿囊膜血管化的抑制作用在存在不同肿瘤异种移植物的情况下被消除。通过尺寸排阻、离子交换色谱以及质谱，我们确定了 GRP-78（一种未折叠蛋白反应的伴侣蛋白）是导致硼替佐米耐药的原因。事实上，多种硼替佐米耐药实体瘤细胞系（PC-3、HRT-18）能够分泌大量 GRP-78，但骨髓瘤细胞系（U266、OPM-2）则不然。重组 GRP-78 赋予内皮细胞和 OPM-2 骨髓瘤细胞对硼替佐米的耐药性。肿瘤细胞中 GRP-78 基因表达的敲低和肿瘤细胞上清液中 GRP-78 蛋白的免疫耗竭恢复了硼替佐米的敏感性。 GRP-78 不结合或复合硼替佐米，但通过细胞外信号相关激酶的磷酸化诱导促存活信号，并抑制内皮细胞中 p53 介导的促凋亡 Bok 和 Noxa 蛋白的表达。根据我们的数据，我们得出结论，不同的实体瘤细胞能够将 GRP-78 分泌到肿瘤微环境中，从而证明了迄今为止未知的硼替佐米耐药机制。 （血。2009；114：3960-3967）
Antiangiogenic effects of the proteasome inhibitor bortezomib were analyzed on tumor xenografts in vivo. Bortezomib strongly inhibited angiogenesis and vascularization in the chicken chorioallantoic membrane. Bortezomib's inhibitory effects on chorioallantoic membrane vascularization were abrogated in the presence of distinct tumor xenografts, thanks to a soluble factor secreted by tumor cells. Through size-exclusion and ion-exchange chromatography as well as mass spectroscopy, we identified GRP-78, a chaperone protein of the unfolded protein response, as being responsible for bortezomib resistance. Indeed, a variety of bortezomib-resistant solid tumor cell lines (PC-3, HRT-18), but not myeloma cell lines (U266, OPM-2), were able to secrete high amounts of GRP-78. Recombinant GRP-78 conferred bortezomib resistance to endothelial cells and OPM-2 myeloma cells. Knockdown of GRP-78 gene expression in tumor cells and immunodepletion of GRP-78 protein from tumor cell supernatants restored bortezomib sensitivity. GRP-78 did not bind or complex bortezomib but induced prosurvival signals by phosphorylation of extracellular signal-related kinase and inhibited p53-mediated expression of proapoptotic Bok and Noxa proteins in endothelial cells. From our data, we conclude that distinct solid tumor cells are able to secrete GRP-78 into the tumor microenvironment, thus demonstrating a hitherto unknown mechanism of resistance to bortezomib. (Blood. 2009;114:3960-3967)