PO-103 Regulation of prostate cancer cell growth and signalling by exercise

Abstract

IntroductionMalignant mesothelioma (MM) is an aggressive cancer of the mesothelium. MM has a poor prognosis with a median post-diagnosis survival of 12 months. Currently, MM is treated with platinum-based chemotherapy, resulting in side-effects to the patient. Hence, efforts have been focused on genetically analysing MM tumours to improve treatment specificity. Genetically, MMs are characterised by the loss of key tumour suppressor genes such as NF2. NF2 functions as a member of the Hippo signalling pathway. The Hippo pathway consists of a tumour-suppressive kinase cascade which inactivates the proto-oncogenic transcription factors YAP and TAZ. NF2 up-regulates the Hippo pathway kinases to reduce the activity of YAP/TAZ. Hence, NF2 mutant MMs may exhibit hyperactivity of YAP/TAZ, driving oncogenic processes. So, YAP/TAZ may be ideal therapeutic targets for treating NF2 mutant MMs.Material and methodsA panel of 7 MM cell lines and one wildtype mesothelial cell line were used to assess the potential for selectively targeting YAP/TAZ to treat MMs with mutations in NF2 or in the Hippo pathway kinases LATS1/2. YAP and TAZ activity was abrogated in the cell lines using siRNA-mediated knockdown or using chemical inhibition with the drug compounds Verteporfin or Simvastatin. The viability of cell lines 96 hours post YAP/TAZ inhibition was measured using an Alamar blue viability assay. Statistical comparisons of cellular responses to YAP/TAZ inhibition were conducted using an unpaired student’s t-test.Results and discussionsThe effect of YAP/TAZ inhibition on the viability of a panel of 7 MM cell lines and a wildtype mesothelial cell line (Met5A) was assessed. Hippo pathway mutant cell lines showed the highest sensitivity to YAP/TAZ knockdown, however, two non-mutant MM cells also showed considerable sensitivity, indicating that there wasn’t a statistically significant dependence of mutant cell lines on YAP/TAZ for viability. Mutant cell lines did not show selective sensitivity to Simvastatin or Verteporfin, suggesting that these compounds may not be ideal treatment options. However, these observations were likely confounded by the heterogeneity of the panel of cell lines. As such, an isogenic system of NF2 mutant Met5A cells was developed to validate the findings.ConclusionBased on our findings, YAP and TAZ may not be ideal targets for treating Hippo pathway mutant MMs. However, the use of an NF2 mutant isogenic MM cell line system will provide a definitive outlook on their feasibility as therapeutic candidates.