Abstract
Epithelial ovarian cancer (EOC) is the most lethal and aggressive gynecological malignancy, and abnormal cellular metabolism significantly contributes to cancer onset and progression. Here, we report that miR-29b negatively regulates AKT2/AKT3 expression, causing HK2/PKM2 downregulation and leading to a decreased Warburg effect and slowed ovarian cancer progression. Compared to normal ovaries, ovaries with epithelial cancer exhibited lower miR-29b expression at both cellular/histological levels. Glucose consumption and lactate production experiments confirmed miR-29b's regulation of EOC metabolism. A luciferase reporter assay confirmed the direct binding of miR-29b to AKT2/AKT3 3' UTRs. miR-29b silencing correlated with increased expression of AKT2/3, pAKT2/3, HK2, and PKM2. Pyruvic acid and NAD+/NADH levels also changed when miR-29b expression was suppressed; this effect could be blocked by specific AKT inhibitors, suggesting the miR-29b-AKT axis regulates the Warburg effect in ovarian cancer. In xenograft mouse models, miR-29b inhibited tumor formation in vivo. In vivo imaging also demonstrated that miR-29b agomir inhibited the relative uptake of 18F-FDG in the xenograft tumors, suggesting that miR-29b over-expression could negatively modulate tumor glucose metabolism in vivo. Taken together, our study suggests that miR-29b regulates the Warburg effect in EOC via AKT2/AKT3 and may provide novel options for future treatments for EOC.