Ulva pertusa lectin 1 delivery through adenovirus vector affects multiple signaling pathways in cancer cells
Ulva pertusa lectin 1 delivery through adenovirus vector affects multiple signaling pathways in cancer cells
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通过腺病毒载体传递石莼凝集素 1 影响癌细胞中的多种信号通路
DOI：
10.1007/s10719-017-9767-6
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发表时间：
2017-08-01
影响因子：
3
通讯作者：
Chen, Jing
中科院分区：
文献类型：
--
作者：
Li, Gongchu;Zhao, Zhenzhen;Chen, Jing
孔石莼凝集素1（Ulva pertusa lectin 1，UPL 1）是海洋绿色海藻孔石莼（Ulva pertusa）中的一种N-乙酰-D-葡萄糖胺（GlcNAc）结合凝集素。外源UPL 1与蛋白质精氨酸甲基转移酶5（PRMT 5）、甲基化体蛋白50（MEP 50）、β-肌动蛋白和β-微管蛋白共定位，表明UPL 1与甲基化体和细胞骨架相互作用。UPL 1通过腺病毒载体（Ad-UPL 1）递送显著诱导肝癌细胞系BEL-7404和Huh 7中的细胞外调节蛋白激酶1/2（ERK 1/2）磷酸化。Ad-UPL 1还以细胞类型依赖的方式影响p38丝裂原活化蛋白激酶（MAPK）和Akt等信号通路。MEK 1/2抑制剂U 0126，以及在较小程度上p38 MAPK抑制剂SB 203580和磷酸肌醇3-激酶（PI 3 K）抑制剂LY 294002，完全消除了由Ad-UPL 1诱导的较高分子量的β-微管蛋白亚型，并显著增强了Ad-UPL 1在Huh 7细胞中的细胞毒性，这表明抑制MEK 1/2、p38 MAPK、PI 3 K可能通过调节β-tubulin的修饰而增强Ad-UPL 1的抗增殖作用。Ad-UPL 1可完全抑制自噬相关因子Beclin 1的表达，但可诱导Huh 7细胞LC 3-II的表达。此外，Ad-UPL 1显著增强饥饿诱导的Huh 7细胞存活抑制。我们的数据阐明了受外源性UPL 1影响的细胞内信号传导途径，并可能为通过腺病毒载体结合生存信号抑制剂递送UPL 1用于癌症治疗提供新的途径。
Ulva pertusa lectin 1 (UPL1) is a N-acetyl-D-glucosamine (GlcNAc) binding lectin in marine green alga Ulva pertusa. Exogenous UPL1 colocalized with protein arginine methyltransferase 5 (PRMT5), methylosome protein 50 (MEP50), beta-actin and beta-tubulin, indicating the interaction of UPL1 with the methylosome and cytoskeleton. UPL1 delivery through adenovirus vector (Ad-UPL1) dramatically induced extracellularly regulated protein kinases 1/2 (ERK1/2) phosphorylation in liver cancer cell lines BEL-7404 and Huh7. Signaling pathways including p38 mitogen-activated protein kinase (MAPK), and Akt were also affected by Ad-UPL1 in a cell type dependent manner. MEK1/2 inhibitor U0126, as well as to a lesser extent p38 MAPK inhibitor SB203580 and phosphoinositide 3-kinase (PI3K) inhibitor LY294002, completely eliminated a higher molecular weight isoform of beta-tubulin induced by Ad-UPL1, and significantly enhanced the cytotoxicity of Ad-UPL1 in Huh7 cells, suggesting that the inhibition of MEK1/2, p38 MAPK, and PI3K enhanced antiproliferative effect of Ad-UPL1 possibly through regulating the modification of beta-tubulin. Ad-UPL1 completely inhibited the expression of autophagy-related factor Beclin1, but induced LC3-II expression in Huh7 cells. In addition, Ad-UPL1 significantly enhanced starvation induced survival suppression in Huh7 cells. Our data elucidated intracellular signaling pathways affected by exogenous UPL1, and may provide insights into a novel way of UPL1 delivery through adenovirus vectors combined with survival signaling inhibitors for cancer treatment.