Abstract from Stem Cells
Glioblastoma multiforme (GBM) ranks amongst the deadliest types of cancer and given this, new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumours and that it clustered with the proliferative subtype. Patients with PLK1-high tumours were more likely to die from their disease suggesting that current therapies are inactive against such tumours. This prompted us to examine its expression in brain tumour initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110–470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumoursphere cultures. PLK1 inhibition suppressed growth, caused G2/M arrest, induced apoptosis and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of GFAP and changes in cellular morphology.
We then knocked-down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, down-regulated SOX2 and induced cell death. Furthermore, BI2536 delayed tumour growth of U251 cells in an orthotopic brain tumour model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells.