TY - JOUR
T1 - Suppression of the ABCA1 Cholesterol Transporter Impairs the Growth and Migration of Epithelial Ovarian Cancer
AU - Gao, Jixuan
AU - Jung, Moonsun
AU - Williams, Rebekka T.
AU - Hui, Danica
AU - Russell, Amanda J.
AU - Naim, Andrea J.
AU - Kamili, Alvin
AU - Clifton, Molly
AU - Bongers, Angelika
AU - Mayoh, Chelsea
AU - Ho, Gwo
AU - Scott, Clare L.
AU - Jessup, Wendy
AU - Haber, Michelle
AU - Norris, Murray D.
AU - Henderson, Michelle J.
N1 - Funding Information:
Funding: This research was funded by the National Health and Medical Research Council (APP1016699 and APP1132608 to M.H. and M.D.N.), Cancer Institute NSW (10/TPG/1-03 to M.H. and M.D.N.) and Cancer Australia (1067110 to M.J.H.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/2
Y1 - 2022/4/2
N2 - 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.
AB - 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.
KW - ABCA1
KW - cholesterol
KW - epithelial ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=85127735583&partnerID=8YFLogxK
U2 - 10.3390/cancers14081878
DO - 10.3390/cancers14081878
M3 - Article
C2 - 35454786
AN - SCOPUS:85127735583
VL - 14
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 1878
ER -