Abstract
Cancer cells exhibit the reprogrammed metabolism mainly via aerobic glycolysis, a phenomenon known historically as the Warburg effect; however, the underlying mechanisms remain largely unknown. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in aerobic glycolysis of human epithelial ovarian cancer (EOC) and its molecular mechanisms. Our data showed that aberrant expression of FOXM1 significantly contributed to the reprogramming of glucose metabolism in EOC cells. Aerobic glycolysis and cell proliferation were down-regulated in EOC cells when FOXM1 gene expression was suppressed by RNA interference. Moreover, knockdown of FOXM1 in EOC cells significantly reduced glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. FOXM1 bound directly to the GLUT1 and HK2 promoter regions and regulated the promoter activities and the expression of the genes at the transcriptional level. This reveals a novel mechanism by which glucose metabolism is regulated by FOXM1. Importantly, we further demonstrated that the expression levels of FOXM1, GLUT1 and HK2 were significantly increased in human EOC tissues relative to normal ovarian tissues, and that FOXM1 expression was positively correlated with GLUT1 and HK2 expression. Taken together, our results show that FOXM1 promotes reprogramming of glucose metabolism in EOC cells via activation of GLUT1 and HK2 transcription, suggesting that FOXM1 may be an important target in aerobic glycolysis pathway for developing novel anticancer agents.
Highlights
According to new statistics offered by the American Cancer Society, ovarian cancer is the fifth most common cause of cancer-related death among women and the most lethal gynecologic cancer in the United States [1]
We examined the effect of Forkhead box protein M1 (FOXM1) knockdown on the expression of a number of key genes involved in glycolysis, including glucose transporter 1 (GLUT1), GLUT4, hexokinase 2 (HK2), lactate dehydrogenase isoform A (LDHA), and so on
Quantitative real-time PCR analyses showed that GLUT1 and HK2 mRNA levels were significantly decreased by FOXM1 knockdown in A2780 and SKOV3 cells (Figure 1A and 1B)
Summary
According to new statistics offered by the American Cancer Society, ovarian cancer is the fifth most common cause of cancer-related death among women and the most lethal gynecologic cancer in the United States [1]. EOC constitutes approximately 90% of ovarian malignancies, and most patients present with widely metastatic disease at diagnosis and this results in a poor prognosis This necessitates a better understanding of the molecular mechanisms underlying EOC, which may play an important role in developing better early diagnostic and prognostic biomarkers. In patients with epithelial ovarian cancer, 2-[18F] fluoro-2-deoxyD-glucose (18F-FDG) positron emission tomography/ computed tomography (PET/CT) is useful in diagnosing, staging, detecting recurrent lesions, and monitoring treatment response [10,11,12,13]. It is still not completely clear why increased glucose metabolism is selected by proliferating cancer cells. Recent studies demonstrated that alterations in signaling pathways, which serve to increase glucose uptake, glycolysis, angiogenesis and stress resistance, may contribute to the reprogramming of glucose metabolism [14,15,16]
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