| dc.description.abstract | Research in the area of hallmarks of cancer has opened the possibility of designing novel therapeutic interventions based on modulating these cancer properties. A process that has not yet been targeted therapeutically in prostate cancer (PCa) is the epithelial-mesenchymal transitions (EMT), which is the reversible interchanges between an epithelial phenotype and a mesenchymal. Previously, in a repositioning screen using a reporter based on FGFR2 splicing, three new chemicals that modulate EMT in PCa (named LLSOs) have been found (Li et al., 2022). The aim of this study is to investigate the impact of these LLSOs on the properties of PCa cells both in vitro and in vivo. Additionally, this project seeks to elucidate the underlying mechanisms by which these compounds induce MET and switch FGFR2 splicing.
This study assessed alterations in various properties of different PCa cell lines following treatment with LLSOs through both in vitro and in vivo assays. The functional effect of these chemicals in vitro on various PCa cell lines was investigated through the implementation of cell viability assay, migration assay, apoptosis assay and EMT markers staining assay. The in vivo assay was examined by administering LLSO3 intraperitoneally in a xenograft model of PCa in nude mice. Moreover, the mechanisms of three LLSOs were investigated with regard to their impact on EMT markers and FGFR2 splicing through targeted inhibition of specific steps within potential pathways.
These LLSOs exhibited varying effects on the properties of cancer cell lines but all of them inhibited the migration of PCa cells, in line with modulating EMT and switching FGFR2 splicing. LLSO3 also exhibited a significant inhibitory effect on tumour growth in vivo, concomitant with an increase in the expression level of E-cadherin. Further investigation was conducted to obtain mechanistic insights into the LLSO compounds. Knowing the molecular heterogeneity of prostate cancer, I probed this mechanism in several cell lines - PC3, LNCaP and DU145. Some of the signalling pathways used by these three LLSO compounds to regulate EMT and switch FGFR2 splicing in PCa cells have been identified in this project: LLSO1 (NNC-55-0396 dihydrochloride, a highly selective T-type calcium channel blocker); LLSO2 (Nemadipine, an L-type Ca-channel antagonist); and LLSO3 (Naltrexone, an opioid antagonist). | en_GB |
