British journal of cancer · 2025
Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma.
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Schelch Karin, Maach Nadine, Hashim Muhammad, Zitta Benjamin, Kirchhofer Dominik, Timelthaler Gerald, Solta Anna, Emminger Dominik, Kopatz Verena, Hoda Mir A, Berger Walter, Aigner Clemens, Dome Balazs, Reid Glen, Grusch Michael
Аннотация
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.
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.