Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma.

Abstract

Simple SummaryHigh-grade serous carcinoma (HGSOC) is the most aggressive subtype of ovarian cancer and accounts for the vast majority of advanced stage cases. Intracellular accumulation of lipids as lipid droplets has been recognized as one of the characteristics of cancers and implicated in poor prognosis of several cancers, such as human melanomas. Here, we investigated the relationship between prognosis and lipid accumulation in HGSOC, and found that enhanced lipid accumulation in HGSOC tissues significantly correlated with poor prognosis. In cell-based assays with human ovarian cancer cells, we provide evidence that aerobic glycolysis, which is one of the characteristic metabolic abnormalities in cancer, induced lipid accumulation within cancer cells and targeting the lipid accumulation could suppress cancer cell proliferation. Thus, our results propose abnormal lipid accumulation as a negative indicator of HGSOC prognosis and a novel therapeutic target.High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.