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

Jixuan Gao, Moonsun Jung, Rebekka T. Williams, Danica Hui, Amanda J. Russell, Andrea J. Naim, Alvin Kamili, Molly Clifton, Angelika Bongers, Chelsea Mayoh, Gwo Ho, Clare L. Scott, Wendy Jessup, Michelle Haber, Murray D. Norris, Michelle J. Henderson

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1878
Number of pages17
JournalCancers
Volume14
Issue number8
DOIs
Publication statusPublished - 2 Apr 2022
Externally publishedYes

Keywords

  • ABCA1
  • cholesterol
  • epithelial ovarian cancer

Cite this