Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways
Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways
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DOI：
10.1073/pnas.061031898
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Woude, GFV
中科院分区：
文献类型：
--
作者：
Duesbery, NS;Resau, J;Woude, GFV
致死因子是一种蛋白酶，它是炭疽杆菌外毒素的一种成分，可裂解许多丝裂原激活的蛋白激酶激酶 (MEK)。鉴于 MEK 信号在肿瘤发生中的重要性，我们评估了炭疽致死毒素 (LeTx) 对肿瘤细胞的影响。 LeTx 在抑制 V12 H-ras 转化的 NIH 3T3 细胞中丝裂原激活蛋白激酶的激活方面非常有效。在体外，用 LeTx 处理转化细胞使它们恢复到未转化的形态，并抑制它们在软琼脂中形成集落和侵入基质胶的能力，而不会显着影响细胞增殖。在体内，LeTx 抑制植入无胸腺裸鼠体内的 ras 转化细胞的生长（在某些情况下会导致肿瘤消退），其浓度不会引起明显的动物毒性。出乎意料的是，LeTx 还大大减少了肿瘤新生血管形成。这些结果表明 LeTx 有效抑制 ras 介导的肿瘤生长，是一种潜在的抗肿瘤治疗方法。
Lethal factor is a protease, one component of Bacillus anthracis exotoxin, which cleaves many of the mitogen-activated protein kinase kinases (MEKs). Given the importance of MEK signaling in tumorigenesis, we assessed the effects of anthrax lethal toxin (LeTx) on tumor cells. LeTx was very effective in inhibiting mitogen-activated protein kinase activation in V12 H-ras-transformed NIH 3T3 cells. In vitro, treatment of transformed cells with LeTx caused them to revert to a nontransformed morphology, and inhibited their abilities to form colonies in soft agar and to invade Matrigel without markedly affecting cell proliferation. In vivo, LeTx inhibited growth of ras-transformed cells implanted in athymic nude mice tin some cases causing tumor regression) at concentrations that caused no apparent animal toxicity. Unexpectedly, LeTx also greatly decreased tumor neovascularization. These results demonstrate that LeTx potently inhibits ras-mediated tumor growth and is a potential antitumor therapeutic.