Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78.
Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78.
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纤溶酶原 kringle 5 通过调节 HIF-1 α 和 GRP78 抑制胃癌
DOI：
10.1038/cddis.2017.528
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发表时间：
2017-10-26
影响因子：
9
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Fang S;Hong H;Li L;He D;Xu Z;Zuo S;Han J;Wu Q;Dai Z;Cai W;Ma J;Shao C;Gao G;Yang X
抑制肿瘤血管生成在抗肿瘤治疗中具有重要作用。然而，最近的研究表明，抗血管生成治疗可能导致葡萄糖相关蛋白78（GRP 78）相关的抗凋亡抵抗。本研究旨在阐明纤溶酶原kringle 5（K5）通过靶向低氧诱导因子1α（HIF-1α）和GRP 78对肿瘤血管生成和诱导凋亡的双重作用。采用免疫共沉淀法和蛋白质印迹法检测HIF-1α的泛素化，分析血管生成和凋亡相关蛋白。K5通过在缺氧条件下上调von Hippel-Lindau蛋白，促进sumo/ubiquitin介导的HIF-1α蛋白酶体降解，导致血管内皮生长因子减少，从而抑制肿瘤血管生成。此外，K5通过下调磷酸化细胞外调节蛋白激酶降低GRP 78表达，导致caspase-7裂解和肿瘤细胞凋亡。阻断电压依赖性阴离子通道可阻断K5对HIF-1α和GRP 78的作用。K5通过抑制肿瘤血管生成和细胞凋亡，显著抑制胃癌移植瘤的生长。这种双重作用表明，K5可能是一种有前途的生物治疗剂，用于治疗胃癌，特别是在表现出GRP 78诱导的患者中。
Inhibition of tumour angiogenesis has an important role in antitumour therapy. However, a recent study indicates that antiangiogenesis therapy may lead to glucose-related protein 78 (GRP78) associated antiapoptotic resistance. The present study aims to elucidate the dual effects of plasminogen kringle 5 (K5) on tumour angiogenesis and apoptosis induction by targeting hypoxia-inducible factor 1α (HIF-1α) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1α and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1α by upregulating von Hippel-Lindau protein under hypoxia, resulting in the reduction of vascular endothelial growth factor and thus suppressing tumour angiogenesis. Furthermore, K5 decreased GRP78 expression via downregulation of phosphorylated extracellular-regulated protein kinase, leading to caspase-7 cleavage and tumour cell apoptosis. Blocking voltage-dependent anion channel abrogated the effects of K5 on both HIF-1α and GRP78. K5 significantly inhibited the growth of gastric carcinoma xenografts by inhibiting both angiogenesis and apoptosis. The dual effects suggest that K5 might be a promising bio-therapeutic agent in the treatment of gastric cancer, particularly in patients who exhibit the induction of GRP78.
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影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
4
作者：
Cai, WB;Ma, JF;Gao, GQ
通讯作者：
Gao, GQ
影响因子：
4.8
作者：
Gao, GQ;Li, Y;Ma, JX
通讯作者：
Ma, JX
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Lee, Eunfung;Nichols, Peter;Lee, Amy S.
通讯作者：
Lee, Amy S.