Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism.

摘要: Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It well recognized to regulate glycolysis target for therapy. However, how tumor cells adapt grow absence HIF1α poorly understood an important concept understand developing targeted therapies flexibility metabolic via alternative pathways. We analyzed pathways that allow survive hypoxic stress HIF1α, using HCT116 colon cell line with deleted versus control. Spheroids were used provide 3D model gradients. conducted metabolomic, transcriptomic, proteomic analysis integrated results. These showed surprisingly three-dimensional growth, regulatory step Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained through upregulation GLUT14, not previously this role. Finally, there was marked adaptation change phosphocreatine energy pathways, which made susceptible inhibition creatine metabolism conditions. Overall, our studies show complex can bypass but it targetable provides new insight into involved growth. IMPLICATIONS: Under HIF1 blockade, their GLUT14 transporter providing avenues drug targeting.