Poster Presentation 30th Lorne Cancer Conference 2018

Targeting YB-1 controls drug response via distinct mechanisms in malignant pleural mesothelioma (#177)

Thomas G Johnson 1 2 , Karin Schelch 1 2 , Kadir H Sarun 1 , Yuen Y Cheng 1 2 , Annette Lasham 3 , Nico Van Zandwijk 2 , Glen Reid 1 2
  1. The Asbestos Diseases Research Institute, Sydney, Concord, NSW, Australia
  2. Faculty of Medicine, The University of Sydney, Sydney, NSW, Australia
  3. School of Medical Sciences, The University of Auckland, Auckland, New Zealand

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.