PDF(Pubmed)
Abstract：
Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that inhibit protein translation. However, translational and therapeutic approaches to inhibit protein synthesis in tumors are limited. In this work, we identified that reactive oxygen species, which are generated by a wide range of chemotherapy and other drugs, inhibit protein synthesis and reduce the level of critical proteins that support tumorigenesis in Ewing sarcoma cells. In particular, we identified that both hydrogen peroxide and auranofin, an inhibitor of thioredoxin reductase and regulator of oxidative stress and reactive oxygen species, activate the repressor of protein translation 4E-BP1 and reduce the levels of the oncogenic proteins RRM2 and PLK1 in Ewing and other sarcoma cell lines. These results provide novel insight into the mechanism of how ROS-inducing drugs target cancer cells via inhibition of protein translation and identify a mechanistic link between ROS and the DNA replication (RRM2) and cell cycle regulatory (PLK1) pathways.
摘要：
需要新的治疗方法来治疗尤因肉瘤肿瘤。我们先前确定尤文肉瘤细胞系对抑制蛋白质翻译的药物敏感。然而,在肿瘤中抑制蛋白质合成的翻译和治疗方法是有限的。在这项工作中,我们发现了活性氧，由多种化疗和其他药物产生，抑制蛋白质合成并降低支持尤文肉瘤细胞肿瘤发生的关键蛋白质的水平。特别是,我们发现过氧化氢和金诺芬，硫氧还蛋白还原酶的抑制剂和氧化应激和活性氧的调节剂，激活蛋白质翻译4E-BP1的阻遏物，并降低尤因和其他肉瘤细胞系中致癌蛋白RRM2和PLK1的水平。这些结果提供了对ROS诱导药物如何通过抑制蛋白质翻译靶向癌细胞的机制的新见解，并确定了ROS与DNA复制（RRM2）和细胞周期调节（PLK1）途径之间的机制联系。
