No abstract

Cancer cells need to meet the metabolic demands of rapid cell growth within a continually changing microenvironment. Genetic mechanisms for reprogramming cellular metabolism toward proliferative, pro-survival pathways are well-reported. However, post-translational mechanisms, which would enable more rapid, reversible adaptations of cellular metabolism in response to protein signaling or environmental sensing systems, are less well understood. Here we demonstrate that the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) is a key metabolic regulator of glucose metabolism. O-GlcNAc is dynamically induced at Ser529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibits PFK1 activity and redirects the flux of glucose from glycolysis through the pentose phosphate pathway (PPP), thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal an unexpected mechanism for the regulation of metabolic enzymes and pathways, and pinpoint a new therapeutic approach for combating cancer.

Supplementary Figure 1. Expression levels of EGR-1, GRASP55 and eIF4G following kainic acid treatment of rats. Cortical neuronal lysates were obtained 6 h post-injection of kainic acid or PBS. EGR-1 expression changed by 1.8 ± 0.2, GRASP55 expression by 0.61 ± 0.09 and eIF4G expression by 1.5 ± 0.1. Data represent the mean ± s.d. for 3 experiments.