Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells
Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells
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DOI：
10.1038/s41467-019-11909-z
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发表时间：
2019-09-09
影响因子：
16.6
通讯作者：
Samstag, Yvonne
中科院分区：
文献类型：
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作者：
Balta, Emre;Hardt, Robert;Samstag, Yvonne
几种抗肿瘤疗法通过增加肿瘤微环境中的活性氧（ROS）起作用。在这里，我们发现l -活素（LPL）是一种已建立的肿瘤标志物，可被ros诱导的Cys101上的硫醇氧化可逆调节，Cys101与Cys42形成二硫桥。LPL还原是由Thioredoxin1 （TRX1）系统介导的，如TRX1捕获、TRX1敲低和用金烷fin阻断Thioredoxin1还原酶（TRXR1）所示。LPL氧化降低了它的动作捆绑能力。使用LPL- rogfp - orp1融合蛋白的比例成像和基于二聚酮的接近结扎试验（PLA）显示，LPL氧化主要发生在基于肌动蛋白的细胞挤压中，并强烈抑制肿瘤细胞的细胞扩散和丝状延伸的形成。这种作用伴随着肿瘤细胞迁移、侵袭和细胞外基质（ECM）降解的减少。由于LPL氧化发生在用金酰黄酮或γ辐照治疗肿瘤后，这可能是一种分子机制，有助于氧化还原改变疗法治疗肿瘤的有效性。
Several antitumor therapies work by increasing reactive oxygen species (ROS) within the tumor micromilieu. Here, we reveal that L-plastin (LPL), an established tumor marker, is reversibly regulated by ROS-induced thiol oxidation on Cys101, which forms a disulfide bridge with Cys42. LPL reduction is mediated by the Thioredoxin1 (TRX1) system, as shown by TRX1 trapping, TRX1 knockdown and blockade of Thioredoxin1 reductase (TRXR1) with auranofin. LPL oxidation diminishes its actin-bundling capacity. Ratiometric imaging using an LPL-roGFP-Orp1 fusion protein and a dimedone-based proximity ligation assay (PLA) reveal that LPL oxidation occurs primarily in actin-based cellular extrusions and strongly inhibits cell spreading and filopodial extension formation in tumor cells. This effect is accompanied by decreased tumor cell migration, invasion and extracellular matrix (ECM) degradation. Since LPL oxidation occurs following treatment of tumors with auranofin or gamma-irradiation, it may be a molecular mechanism contributing to the effectiveness of tumor treatment with redox-altering therapies.