Malignant pleural mesothelioma (MPM) is an aggressive malignancy and current therapy is essentially palliative. YB-1 is a multifunctional oncoprotein widely accepted to play a role in the growth of many tumours. High expression of YB-1 is associated with poor patient outcome in tumours including NSCLC and is related to increased chemoresistance. YB-1 has been implicated in suppressing apoptotic pathways in breast cancer and disrupting the cell-cycle via transcriptionally regulating cyclins A, B1 and D1 in multiple other malignancies. We recently found YB-1 to be overexpressed in MPM cells and that siRNA-mediated knockdown inhibited growth. Here we investigate the mechanisms behind the role of YB-1 in MPM cell growth and subsequent effects on drug resistance.
YB-1 was overexpressed in these cells compared to the immortalised mesothelial MeT-5A, determined via Western Blot. YB‑1 levels were also upregulated in cells with acquired drug resistance, compared to parental cells. Proliferation and colony formation assays showed YB-1 siRNA caused significant growth inhibition of MSTO and VMC23 cells (p<0.05). TALI apoptosis assays revealed that growth inhibition was due to apoptosis and necrosis in MSTO cells but not in VMC23, in which flow cytometry showed that cell-cycle arrest was the cause of growth inhibition. Interestingly, YB-1 knockdown in MSTO cells resulted in a sensitisation to cisplatin, gemcitabine and vinorelbine, but increased resistance to these drugs in VMC23. This suggests that there is a cell-type dependent link between the role of YB-1 in regulation of growth and the effect of its silencing on innate drug resistance in MPM cells. When acting upon apoptotic pathways, YB-1 knockdown sensitised MPM cells to chemotherapy. In other cases, YB-1-mediated cell-cycle arrest resulted in heightened resistance. Finally, YB-1 is upregulated in cells with acquired drug resistance, indicating that it plays an important role in the acquired resistance to cisplatin, gemcitabine and vinorelbine in MPM.