A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt
A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt
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DOI：
10.1007/s10456-011-9220-6
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发表时间：
2011-09-01
期刊：
影响因子：
9.8
通讯作者：
Das Gupta, Tapas K.
中科院分区：
文献类型：
--
作者：
Mehta, Rajeshwari R.;Yamada, Tohru;Das Gupta, Tapas K.
天青的50-77个氨基酸(P28)是从铜绿假单胞菌中分离出来的128个氨基酸的铜还蛋白，它是天青优先渗透癌细胞的主要原因。我们现在报道，在多种异种移植模型中，p28还优先穿透人脐静脉内皮细胞(HUVEC)，与小窝蛋白-1和VEGFR-2共定位，并抑制血管内皮生长因子和碱性成纤维细胞生长因子诱导的迁移、毛细血管形成和新生血管生成。P28在HUVEC中的抗血管生成作用与剂量相关的对VEGFR-2激酶活性的非竞争性抑制有关。然而，与其他抑制VEGFR-2激酶的抗血管生成药物不同，p28降低了FAK和Akt下游的磷酸化，而FAK和Akt通常在细胞重新定位细胞骨架(F-肌动蛋白)、焦点黏附(FAK和paxlin)和细胞与细胞连接蛋白PECAM-1之前，从而抑制HUVEC的运动和迁移。PFAK和PAKT水平的降低表明p28诱导pFAK介导的HUVEC运动和迁移的丧失，以及与Akt相关的细胞基质附着和存活的减少。P28对内皮细胞的这种新的、直接的抗血管生成作用可能会在进入II期临床试验时增强该原型肽对肿瘤细胞增殖的细胞周期抑制和凋亡特性。
Amino acids 50-77 (p28) of azurin, a 128 aa cupredoxin isolated from Pseudomonas aeruginosa, is essentially responsible for azurin's preferential penetration of cancer cells. We now report that p28 also preferentially penetrates human umbilical vein endothelial cells (HUVEC), co-localized with caveolin-1 and VEGFR-2, and inhibits VEGF- and bFGF-induced migration, capillary tube formation and neoangiogenesis in multiple xenograft models. The antiangiogenic effect of p28 in HUVEC is associated with a dose-related non-competitive inhibition of VEGFR-2 kinase activity. However, unlike other antiangiogenic agents that inhibit the VEGFR-2 kinase, p28 decreased the downstream phosphorylation of FAK and Akt that normally precedes cellular repositioning of the cytoskeletal (F-actin), focal adhesion (FAK and paxillin), and cell to cell junction protein PECAM-1, inhibiting HUVEC motility and migration. The decrease in pFAK and pAkt levels suggests that p28 induces a pFAK-mediated loss of HUVEC motility and migration and a parallel Akt-associated reduction in cell matrix attachment and survival. This novel, direct antiangiogenic effect of p28 on endothelial cells may enhance the cell cycle inhibitory and apoptotic properties of this prototype peptide on tumor cell proliferation as it enters a Phase II clinical trial.