Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models.

Abstract

Cancer stem cells (CSC) exhibit therapy resistance and drive self-renewal of the tumour, making cancer stem cells an important target for therapy. The PI3K signalling pathway has been the focus of considerable research effort, including in glioblastoma (GBM), a cancer that is notoriously resistant to conventional therapy. Different isoforms of the catalytic sub-unit have been associated with proliferation, migration and differentiation in stem cells and cancer stem cells. Blocking these processes in CSC would improve patient outcome. We examined the effect of isoform specific PI3K inhibitors in two models of GBM CSC, an established GBM stem cell line 08/04 and a neurosphere formation model. We identified the dominant catalytic PI3K isoform for each model, and inhibition of the dominant isoform blocked AKT phosphorylation, as did pan-PI3K/mTOR inhibition. Analysis of SOX2, OCT4 and MSI1 expression revealed that inhibition of the dominant p110 subunit increased expression of cancer stem cell genes, while pan-PI3K/mTOR inhibition caused a similar, though not identical, increase in cancer stem cell gene expression. This suggested that PI3K inhibition enhanced, rather than blocked, CSC activity. Careful analysis of the response to specific isoform inhibition will be necessary before specific subunit inhibitors can be successfully deployed against GBM CSC.