Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells

Emre Balta, Robert Hardt, Jie Liang, Henning Kirchgessner, Christian Orlik, Beate Jahraus, Stefan Hillmer, Stefan Meuer, Katrin Hübner, Guido H. Wabnitz and Yvonne Samstag ()
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Emre Balta: Heidelberg University Hospital
Robert Hardt: Heidelberg University
Jie Liang: Heidelberg University Hospital
Henning Kirchgessner: Heidelberg University Hospital
Christian Orlik: Heidelberg University Hospital
Beate Jahraus: Heidelberg University Hospital
Stefan Hillmer: Heidelberg University
Stefan Meuer: Heidelberg University Hospital
Katrin Hübner: Heidelberg University Hospital
Guido H. Wabnitz: Heidelberg University Hospital
Yvonne Samstag: Heidelberg University Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11909-z

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