Investigating pathways in tumour cell migration and invasion in response to novel isoquinolinone compounds

Abstract The ability of cancer cells to disseminate from a primary tumour and invade via the breaching of surrounding tissue vasculature is a hallmark of the metastatic phenotype. Cancer cells are highly dynamic adopting a wide range of mechanisms in order to accomplish this enhanced migrational activity. This study looks at the mechanisms behind enhanced migration and invasion in vitro in two highly aggressive cell lines in response to the heterocyclic aromatic organic Isoquinolinone compounds. Here we show that the structurally similar A5 and A3 compounds reduce adhesion of MDA-MB-231 cells to Fibronectin, Matrigel, and Type I collagen which was paralleled in A5 treated HT1080 cells on these matrix components. Compound A5 also induced 2D migration of MDA-MB-231 cells on all matrix substrates. Cell movement of MDA-MB-231 cells through 3D matrices was modestly enhanced by A5 and significantly enhanced by A3. Using gene expression arrays we were able to identify fifteen genes whose expression was regulated by the isoquinolinone compounds and heavily implicated in the process of cell motility. Moreover, we established that these genes are differentially regulated by the compounds over a 24 hour period with expression typically being more enhanced at the earlier time points of 4- and 8- hours and suppressed at 24 hours. The main findings presented in this thesis reveal many proteins involved in cell motility that have not been studied in MDA-MB-231 or HT1080 cells. These results lend support that compound treated cell lines activate several pathways in cell migration and invasion that warrant further investigation to elucidate the precise mechanism of these proteins involved and to develop novel inhibitors for some of the more obscurely studied, but heavily implicated proteins such as RhoQ