Suppression of the ABCA1 Cholesterol Transporter Impairs the Growth and Migration of Epithelial Ovarian Cancer.

Abstract

Simple SummaryEpithelial ovarian cancer (EOC) is the most lethal gynaecological cancer. Over 80% of cases have already spread at diagnosis, and these patients face a five-year survival rate of 35%. EOC cells often spread to the greater omentum, an abdominal fat pad. Here, EOC cells take-up cholesterols. Excessive amounts of cholesterol are lethal; thus, we proposed that the ABCA1 cholesterol transporter exports cholesterol from serous EOC cells to maintain cholesterol balance. Indeed, we found that reducing the level of ABCA1 could suppress serous EOC growth in two-dimensional as well as three-dimensional cell culture and also hindered their migration, a key process required for cancer spread. We also identified drugs that impair EOC cell growth by inhibiting cholesterol export. Our data demonstrate that disrupting the cholesterol balance by targeting ABCA1 may be an effective treatment strategy for EOC patients.Background: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with over 80% of cases already disseminated at diagnosis and facing a dismal five-year survival rate of 35%. EOC cells often spread to the greater omentum where they take-up cholesterol. Excessive amounts of cholesterol can be cytocidal, suggesting that cholesterol efflux through transporters may be important to maintain homeostasis, and this may explain the observation that high expression of the ATP-binding cassette A1 (ABCA1) cholesterol transporter has been associated with poor outcome in EOC patients. Methods: ABCA1 expression was silenced in EOC cells to investigate the effect of inhibiting cholesterol efflux on EOC biology through growth and migration assays, three-dimensional spheroid culture and cholesterol quantification. Results: ABCA1 suppression significantly reduced the growth, motility and colony formation of EOC cell lines as well as the size of EOC spheroids, whilst stimulating expression of ABCA1 reversed these effects. In serous EOC cells, ABCA1 suppression induced accumulation of cholesterol. Lowering cholesterol levels using methyl-B-cyclodextrin rescued the effect of ABCA1 suppression, restoring EOC growth. Furthermore, we identified FDA-approved agents that induced cholesterol accumulation and elicited cytocidal effects in EOC cells. Conclusions: Our data demonstrate the importance of ABCA1 in maintaining cholesterol balance and malignant properties in EOC cells, highlighting its potential as a therapeutic target for this disease.