Reactive Oxygen Species Drive Cell Migration and PD-L1 Expression via YB-1 Phosphorylation in Pleural Mesothelioma

Our plain-English summary of Reactive Oxygen Species Drive Cell Migration and PD-L1 Expression via YB-1 Phosphorylation in Pleural Mesothelioma, by M. Hashim, G. Timelthaler, D. Kirchhofer, et al (Antioxidants, 2026).

The study

• Authors: M. Hashim, G. Timelthaler, D. Kirchhofer, B.I. Kudlacek, B. Mosleh, K. Sinn, E.M. Awad, M.A. Hoda, B. Grasl-Kraupp, B. Dome, W. Berger, G. Krupitza, K. Schelch, M. Grusch
• Journal: Antioxidants
• Published: 2026;15(1)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Reactive oxygen species (ROS)-induced aberrant oncogenic signalling has been proposed to mediate the progression and development of pleural mesothelioma (PM). In this study, we demonstrate how ROS promote oncogenic signalling, especially in the context of cell migration and immune evasion via YB-1 phosphorylation in mesothelial and PM cell models. Xanthine (X)- and xanthine oxidase (XO)-generated ROS exposure led to increased migration and a more elongated cell shape in mesothelial and PM cells in live-cell videomicroscopy analyses. These effects were associated with the enhanced phosphorylation of ERK, AKT, and YB-1 and the elevated gene expression of PD-L1 and PD-L2, which were analysed with immunoblotting and quantitative real-time RT-PCR, respectively. The pharmacological inhibition of AKT (ipatasertib), MEK (trametinib), and RSK (BI-D1870) resulted in the reversal of ROS-induced effects, with the strongest effects observed upon the inhibition of YB-1 phosphorylation by BI-D1870. The results suggest that ROS exposure has a strong impact on cell migration and immune evasion not only in PM cells but also in mesothelial cells, from which PM arises. Interfering with ROS-responsive kinase pathways, particularly YB-1 phosphorylation, could counteract pro-migratory and immune-evasive effects in PM.

In plain English

This was a laboratory study of human cells grown in dishes, not of people or animals. The authors used two non-cancerous mesothelial cell lines (NP2i and Met5A) and two pleural mesothelioma cell lines (MSTO-211H and SPC212). They did not use asbestos fibres. Instead, they exposed the cells to reactive oxygen species (ROS), which are chemically reactive forms of oxygen, made by mixing xanthine with xanthine oxidase. They examined the effects after 24 hours. At the higher dose, cells in all four lines moved significantly farther and became more elongated. Phosphorylation, a chemical modification, of three signalling proteins (ERK, AKT and YB-1) increased. Messenger RNA for PD-L1, a protein linked to immune evasion, rose by up to 4-fold, and PD-L2 also rose. Drugs blocking these signalling pathways reversed several effects. BI-D1870 had the strongest effect on YB-1 phosphorylation and reduced migration in all four lines. The authors concluded that ROS exposure can contribute to enhanced cell migration and PD-L1 increase at the mRNA level. They noted they had no evidence from living organisms.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture experiment
• Who was studied: Four human cell lines: two mesothelial lines (NP2i, an immortalised form of normal pleural mesothelial cells, and the non-malignant Met5A) and two pleural mesothelioma lines (MSTO-211H and SPC212); experiments done in triplicate
• Exposure: Reactive oxygen species (superoxide anions and hydrogen peroxide) generated by xanthine/xanthine oxidase. The low dose was 1 µg/mL xanthine with 0.1 µg/mL xanthine oxidase and the high dose was 20 µg/mL with 2 µg/mL, compared with a vehicle control. No asbestos fibres were used. The cells were also treated with the inhibitors ipatasertib (AKT), trametinib (MEK) and BI-D1870 (RSK) at 10 µM, and in mesothelioma cells with SU056 (YB-1)
• Main results:
  • Xanthine/xanthine oxidase raised ROS levels inside the cells in a dose-dependent way in both mesothelial and mesothelioma cell lines. The selected concentrations did not kill cells.
  • At the higher dose, average migrated distance increased significantly in all four cell lines, and cells became more elongated.
  • The higher dose increased phosphorylation of ERK and AKT. YB-1 serine 102 phosphorylation increased at the higher dose but not at the lower dose, in all models, while total YB-1 levels did not change.
  • PD-L1 mRNA increased by up to 4-fold in mesothelial and mesothelioma cells at the higher dose, and PD-L2 was significantly upregulated. TNFRSF9 and VISTA were not significantly affected in any model. PVR rose only in SPC212 and fell in NP2i.
  • Effects of the inhibitors on ROS-induced migration differed. Ipatasertib had a relatively weak effect in NP2i and SPC212 and no significant effect in the other two lines. Trametinib strongly reduced migration in three of four lines (all except Met5A). BI-D1870 strongly reduced migration in all four lines.
  • BI-D1870 had the strongest inhibiting effect on YB-1 phosphorylation. Trametinib completely inhibited ERK phosphorylation and strongly reduced YB-1 phosphorylation.
  • Trametinib and BI-D1870 showed a tendency to reduce PD-L1 and PD-L2 mRNA in both mesothelioma lines and in NP2i. Ipatasertib showed a tendency to further increase both in all models except NP2i.
  • The YB-1 inhibitor SU056 reduced cell migration in both mesothelioma cell lines.
• The authors' conclusion: The authors concluded that ROS exposure of mesothelial and pleural mesothelioma cells can contribute to enhanced cell migration and to increased PD-L1 at the mRNA level. Their proposed model, in which phosphorylated YB-1 moves to the nucleus and switches on PD-L1/PD-L2, is presented as hypothetical and untested.
• Limitations the authors state:
  • No evidence from living organisms (in vivo).
  • The experiments cannot separate the effects of superoxide anions from those of hydrogen peroxide.
  • Immune checkpoint proteins were measured only as mRNA, not as protein.
  • RSK targets other than YB-1 may account for the effects of the RSK inhibitor.
  • YB-1 nuclear translocation and promoter binding were not tested.
  • In the fast-dividing cancer cells, dividing cells could not be excluded from migration tracking.

Topics

Medical terms in this study, explained in our Lexicon: Reactive Oxygen Species (ROS), PD-L1, Pleural Mesothelioma, Mesothelial Cells.

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• Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma — K. Schelch, N. Maach, et al. (2025)
• Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin — A. Ries, D. Flehberger, et al. (2023)
• Mobilization of iron from urban particulates leads to generation of reactive oxygen species in vitro and induction of ferritin synthesis in human lung epithelial cells — K.R. Smith, A.E. Aust (1997)
• Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species — A. Xu, H. Zhou, et al. (2002)

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