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.

Reactive oxygen species (ROS)-induced aberrant oncogenic signaling has been proposed to mediate the progression and development of pleural mesothelioma (PM). Here we demonstrate how ROS initiates oncogenic signaling 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 more elongated cell shape in mesothelial and PM cells in live cell videomicroscopy analyses. These effects were associated with enhanced phosphorylation of ERK, AKT and YB-1, alongside elevated gene expression of PD-L1 and PD-L2, which were analysed with immunoblotting and quantitative real-time RT-PCR, respectively. Pharmacological inhibition of AKT (ipatasertib), MEK (trametinib) or RSK (BI-D1870) resulted in reversal of ROS-induced effects, with the strongest effects observed upon 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.