Molecular Genetics Program, Jenomic Research Institute, Carmel, CA 93953 , USA.
Front Cell Infect Microbiol. 2013 Aug 13;3:38. doi: 10.3389/fcimb.2013.00038. eCollection 2013.
The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitrous oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11-25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200-250 μM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.
egcSE 由 5 种遗传相关的葡萄球菌肠毒素 SEG、SEI、SElM、SElN 和 SElO 以及 2 种假毒素组成，它们构成了一个操纵子，存在于高达 80%的金黄色葡萄球菌分离株中。一种含有这些蛋白质的制剂最近被用于治疗伴有胸腔积液的晚期肺癌。我们研究了这样一个假设，即 egcSE 诱导一氧化氮（NO）和相关细胞因子的产生，并且这些因子可能参与对广泛的临床相关人类肿瘤细胞的杀伤作用。初步研究表明，egcSE 和 SEA 以浓度依赖的方式激活 T 细胞（范围：11-25%）。用等摩尔量的 egcSE 刺激外周血单核细胞（PBMCs）表达一氧化氮合酶并产生大量亚硝酸盐（范围：200-250 μM），这是 NO 的分解产物；该反应被一氧化氮合酶拮抗剂 NG-单甲基-L-精氨酸（L-NMMA）（0.3 mM）抑制。所有 egcSE 刺激的 PBMCs 的无细胞上清液（CSFs）也同样有效地诱导广泛的人类肿瘤细胞中浓度依赖性的肿瘤细胞凋亡。后一种效应部分归因于 NO 和 TNF-α的产生，因为它分别被 L-NMMA、抗 TNF-α 抗体显著消除，并且两者的组合也被消除。这些 CSFs 对肿瘤细胞的敏感性存在一个层次结构，如下所示：肺癌>骨肉瘤>黑色素瘤>乳腺癌>神经母细胞瘤。值得注意的是，SEG 诱导了与其他 egcSE 和 SEA 相当的强大的 NO/TNFα依赖性肿瘤细胞凋亡激活，尽管其 TNF-α 和 IFN-γ 水平分别比其他 egcSE 和 SEA 低 2 倍和 8 倍。因此，金黄色葡萄球菌产生的 egcSE 诱导一氧化氮合酶，增加的 NO 形成以及 TNF-α 似乎有助于 egcSE 介导的对广泛的人类肿瘤细胞的凋亡。
