A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types
A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types
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DOI：
10.1158/1535-7163.mct-06-0315
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发表时间：
2006-10-01
影响因子：
5.7
通讯作者：
Frankel, Arthur E.
中科院分区：
文献类型：
--
作者：
Abi-Habib, Ralph J.;Singh, Ravibhushan;Frankel, Arthur E.
尿激酶纤溶酶原激活剂（uPA）是一种肿瘤特异性蛋白酶，在多种类型的实体瘤中高度表达，并且在生理条件下很少存在于正常细胞上。由于尿激酶在转移性肿瘤中高表达，因此已使用几种不同的策略来靶向尿激酶系统。这些主要导致肿瘤生长抑制而不是肿瘤消退。采用不同的方法，用尿激酶激活位点替换重组炭疽毒素上的弗林蛋白酶激活位点。由此产生的毒素 PrAgU2/FP59 在体外和体内都具有很强的抗肿瘤作用。在这项研究中，我们证明 PrAgU2/FP59 对多种肿瘤细胞系具有毒性，包括非小细胞肺癌、胰腺癌和基底样乳腺癌细胞系。在少数被发现对 PrAgU2/FP59 具有抗性的细胞系中，大多数细胞系在添加外源 uPA 前体后变得敏感。 PrAgU2/FP59 对正常人体细胞的毒性要小得多。 PrAgU2/FP59 的效力取决于炭疽毒素受体、uPA 受体和 uPA 水平，但不取决于总纤溶酶原激活剂抑制剂-1 水平。在这项研究中，我们证明 PrAgU2/FP59 是一种广泛、高效、高选择性的毒素，能够特异性靶向表达 uPA 的肿瘤细胞，而与这些细胞的来源组织无关。此外，我们还鉴定了三种分子标记：炭疽毒素受体、uPA 和 uPA 受体，它们可用作肿瘤细胞对 PrAgU2/FP59 敏感性的预测因子。
Urokinase plasminogen activator (uPA) is a tumor-specific protease highly expressed in several types of solid tumors and rarely present on normal cells under physiologic conditions. Due to its high expression on metastatic tumors, several different strategies have been used to target the urokinase system. These have mostly led to tumor growth inhibition rather than tumor regression. A different approach was adopted by replacing the furin activation site on a recombinant anthrax toxin with a urokinase activation site. The resulting toxin, PrAgU2/FP59, was highly potent against tumors both in vitro and in vivo. In this study, we show that PrAgU2/FP59 is toxic to a wide range of tumor cell lines, including non-small cell lung cancer, pancreatic cancer, and basal-like breast cancer cell lines. Of the few cell lines found to be resistant to PrAgU2/FP59, most became sensitive upon addition of exogenous pro-uPA. PrAgU2/FP59 was much less toxic to normal human cells. The potency of PrAgU2/FP59 was dependent on anthrax toxin receptor, uPA receptor, and uPA levels but not on total plasminogen activator inhibitor-1 levels. In this study, we show that PrAgU2/FP59 is a wide-range, highly potent, and highly selective toxin that is capable of specifically targeting uPA-expressing tumor cells, independently of the tissue of origin of these cells. Furthermore, we identify three molecular markers, anthrax toxin receptor, uPA, and uPA receptor, which can be used as predictors of tumor cell sensitivity to PrAgU2/FP59.