L 型肌动蛋白结合蛋白的空间氧化作用下调肿瘤细胞基于肌动蛋白的功能。
Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells.
机构信息
Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
Mass Spectrometry Core Facility, Center for Molecular Biology, Heidelberg University, 69120, Heidelberg, Germany.
出版信息
Nat Commun. 2019 Sep 9;10(1):4073. doi: 10.1038/s41467-019-11909-z.
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 γ-irradiation, it may be a molecular mechanism contributing to the effectiveness of tumor treatment with redox-altering therapies.
几种抗肿瘤疗法通过增加肿瘤微环境中的活性氧物种（ROS）来发挥作用。在这里，我们揭示了 L-肌动蛋白（LPL），一种已确立的肿瘤标志物，可被 Cys101 上的 ROS 诱导的巯基氧化可逆调节，该氧化形成与 Cys42 的二硫键。如 TRX1 捕获、TRX1 敲低和用 aur 处理阻断硫氧还蛋白 1 还原酶（TRXR1）所示，LPL 还原由硫氧还蛋白 1（TRX1）系统介导。LPL 氧化会降低其肌动蛋白成束能力。使用 LPL-roGFP-Orp1 融合蛋白和基于二甲基酮的邻近连接测定法（PLA）进行比率成像表明，LPL 氧化主要发生在基于肌动蛋白的细胞外突中，并强烈抑制肿瘤细胞的细胞扩展和丝状伪足延伸形成。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。由于在用 aur 或γ辐射处理肿瘤后发生 LPL 氧化，因此它可能是与氧化还原治疗的肿瘤治疗有效性相关的分子机制。
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