Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma

Our plain-English summary of Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma, by K. Schelch, N. Maach, M. Hashim, et al (British Journal of Cancer, 2025).

The study

• Authors: K. Schelch, N. Maach, M. Hashim, B. Zitta, D. Kirchhofer, G. Timelthaler, A. Solta, D. Emminger, V. Kopatz, M.A. Hoda, W. Berger, C. Aigner, B. Dome, G. Reid, M. Grusch
• Journal: British Journal of Cancer
• Published: 2025;133(9):1391-1400
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The cold-shock domain protein YB-1 is overexpressed in pleural mesothelioma (PM) and was shown to contribute to increased cell migration and platinum resistance.

Methods: Phosphorylation of YB-1 at position serine 102 was analysed by immunohistochemistry, immunofluorescence and immunoblotting in PM tissue specimens and cell lines. Intracellular localisation experiments involved immunoblotting, transfection of fluorescent protein-tagged YB-1 and confocal imaging. YB-1 phosphorylation was inhibited with the RSK inhibitors BI-D1870 and LJH685. Effects of inhibition alone and in combination with radiation or cisplatin treatment were analysed by cell viability assays, clonogenic assays and videomicroscopy-based migration and cell fate map analyses.

Results: YB-1 phosphorylated at serine 102 is present in PM cell lines and tissue. Inhibition of phosphorylation with BI-D1870 reduced YB-1 localisation in the cell nucleus and led to reduced cell viability, clonogenicity, migration and disrupted cell division. Moreover, exposure to BI-D1870 increased the effect of radiation and cisplatin treatment with additive to synergistic effects in PM cell lines and primary cultures.

Conclusions: The serine 102 phosphorylated form of YB-1 contributes to the malignant phenotype of PM. Inhibition of YB-1 phosphorylation warrants further exploration as part of treatment strategies for this devastating disease.

© 2025. The Author(s).

In plain English

This was a laboratory study of a protein called YB-1 in pleural mesothelioma, a cancer the authors describe as often associated with asbestos exposure. Asbestos exposure itself was not studied. Using tissue from six patients at the Medical University of Vienna, the authors found YB-1 carrying a chemical tag (phosphorylation at serine 102) in all mesothelioma specimens analysed, while normal pleura was negative. The tagged form was also present in four mesothelioma cell lines. In cells grown in the laboratory, the drug BI-D1870, which blocks the enzyme RSK, reduced this tagging and lowered the amount of YB-1 in the cell nucleus. It slowed the growth of seven cell lines, with half-inhibiting concentrations from 5.9 µM to 8.9 µM. It also reduced cell movement and disrupted cell division. Combined with cisplatin, it had additive to synergistic effects in cell lines and in three patient-derived cultures. With radiation, growth was lower than predicted in three of four cell lines. The authors noted that drug effects on targets other than YB-1 may have contributed. They concluded that blocking YB-1 phosphorylation warrants further exploration as a treatment approach.

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) study using patient tumour tissue specimens, mesothelioma cell lines and primary cell cultures
• Who was studied: Pleural mesothelioma tissue specimens from six patients and normal pleura, collected at the Medical University of Vienna. Four main cell lines (MSTO-211H, SPC212, MM05, VMC40), a panel of seven cell lines for growth tests, and three primary cultures from surgical samples.
• Exposure: No asbestos exposure was studied. The exposures were laboratory treatments: the RSK inhibitors BI-D1870 and LJH685, alone and combined with cisplatin, 2 Gy radiation, or the Akt inhibitor ipatasertib.
• Main results:
  • Serine 102 phosphorylated YB-1 was found in all mesothelioma tissue specimens analysed; normal pleura was negative
  • In mesothelioma cells, BI-D1870 treatment reduced YB-1 levels in the cell nucleus
  • BI-D1870 inhibited growth of seven mesothelioma cell lines over 72 h, with IC50 values from 5.9 µM to 8.9 µM
  • In cells treated with BI-D1870, doubling time, M-phase length, cell death and cytokinesis failure increased, producing multinucleated cells
  • BI-D1870 significantly reduced cell movement (motility)
  • In MSTO-211H and SPC212 cells, the more specific RSK inhibitor LJH685 gave comparable results, but cytokinesis failure increased less than with BI-D1870
  • BI-D1870 combined with 2 Gy radiation gave lower than predicted growth values in three of four cell lines
  • BI-D1870 combined with cisplatin had additive to synergistic effects in cell lines, strongest in MSTO-211H, with similar efficacy in three primary cultures
• The authors' conclusion: The authors concluded that blocking YB-1 phosphorylation with RSK inhibitors appears to be a promising approach for further exploration of treatment strategies against pleural mesothelioma
• Limitations the authors state:
  • RSK inhibition affects other targets besides YB-1, which may have contributed to the effects of BI-D1870
  • Cytokinesis failure may partly reflect BI-D1870's inhibition of aurora B kinase rather than RSK
  • The tissue cohort was small; a much larger cohort would be needed to assess the effect of prior therapy and links to patient survival
  • The mechanisms linking reduced nuclear YB-1 with cisplatin sensitivity were not established

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Immunohistochemistry, Synergistic Effect.

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• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)
• 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)
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