Endometrial cancer is the most common gynaecological malignancy in the developed world. Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumours themselves has been largely understudied.
Comparing human endometrial tumours and cells to their non-malignant counterparts we found that glycolysis and de novo lipogenesis pathways were highly coupled with the cancer phenotype. One of the most upregulated genes in our human tumour tissues was the glucose transporter 6, GLUT6. Importantly, GLUT6 was expressed exclusively in malignant tissues and cells, and was more closely associated with the cancer phenotype than other hallmark cancer genes including GLUT1, hexokinase 2 and pyruvate kinase M2. GLUT6 has not been functionally investigated in any type of cancer, and we demonstrate for the first time that suppression of GLUT6 expression is sufficient to reduce glucose uptake, glycolysis, and kill endometrial cancer cells.
Endometrial cancer cells were also sensitive to metabolic disruption following treatment with various metabolic inhibitors. In particular, the glycolytic inhibitor, bromopyruvate (BrPA), induced necrosis in endometrial cancer cells via a ROS-independent mechanism, and impaired the growth of endometrial cancer xenografts in vivo. Additionally, we show that BrPA has a more powerful inhibitory effect on lipogenesis than glycolysis, and we identified that the mechanism involves pyruvylation of free coenzyme A.
Overall our study identified GLUT6 and glycolytic-lipogenic pathways as novel liabilities in endometrial cancer that may be exploited for therapeutic intervention