Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression—An in vitro study


Autoři: Vijayalakshmi N. Ayyagari aff001;  Xinjia Wang aff001;  Paula L. Diaz-Sylvester aff001;  Kathleen Groesch aff001;  Laurent Brard aff001
Působiště autorů: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL, United States America aff001;  Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, United States America aff002;  Simmons Cancer Institute at Southern Illinois University School of Medicine, Springfield, IL, United States America aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0228024

Souhrn

Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT-1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.

Klíčová slova:

Apoptosis – Cell cycle and cell division – Cell cycle inhibitors – Cell proliferation – Cell staining – Cholesterol – Ovarian cancer – Reactive oxygen species


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