Cholesterol protects glioblastoma cells against premature mitosis

Abstract

Abstract Glioblastoma is the most common malignant primary tumour with a dismal prognosis. So far, no inhibitors targeting frequently altered pathways in GBM have improved patient survival. Premature entry to mitosis by small molecules that promote cancer cells to bypass the cell-cycle checkpoints have shown potent anti-tumour activity in vitro in a variety of cancers including GBM. We have reproduced these cytotoxic effects in our patient-derived GBM cell lines with the small molecule ME-344 and the Wee1-specific inhibitor AZ1775 both by by clonogenic survival and cell viability assays (EC50 values ranging from 0.003–0.02 μM and 0.2–0.4 μM, respectively). ME-344 and AZ1775 triggered profound morphological and cell cycle effects including mitotic induction, arrest and mitotic catastrophe. Bioinformatic analysis of global mRNA expression of our GBM cell lines stratified by ME-344 sensitivity showed a correlation between high ABCA1 and low cholesterol pathway gene expression with high sensitivity, and vice-versa. Cholesterol is a main component of membranes and is critical for cell growth and mitosis progression. GBM cells rely on cholesterol for survival. Due to the unique metabolic environment of the brain where a nearly unlimited supply of cholesterol is provided by astrocytes, targeting cellular activities regulated by cholesterol might lose their anti-tumour activity. Here we report that cholesterol confers cytoprotection to AZ1775 and ME344 in all GBM cell lines tested. These results suggest that cholesterol can override premature mitotic anti-tumour activity, indicating that mitotic induction and cholesterol inhibition might be a better therapeutic strategy for GBM than either treatment alone.