Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

Abstract

Unique sensitivity of tumor cells to the inhibition of glycolysis makes it a good target for anticancer therapy. Here, we demonstrate that the pharmacologically activated tumor suppressor p53 mediates the inhibition of glycolytic enzymes in cancer cells in vitro and in vivo. We showed that p53 binds to the promoters of metabolic genes and represses their expression, including glucose transporters SLC2A12 (GLUT12) and SLC2A1 (GLUT1). Furthermore, p53-mediated repression of transcriptional factors c-Myc and HIF1alpha, key drivers of ATP-generating pathways in tumors, contributed to ATP production block. Inhibition of c-Myc by p53 mediated the ablation of several glycolytic genes in normoxia, whereas in hypoxia downregulation of HIF1alpha contributed to this effect. We identified SP1 as a p53 transcriptional cofactor cooperating with p53 in the ablation of metabolic genes. Using different approaches, we demonstrated that glycolysis block contributes to the robust induction of apoptosis by p53 in cancer cells. Taken together, our data suggest that tumor-specific reinstatement of p53 function targets Achilles hill of cancer cells, i.e., their dependence on glycolysis, which could contribute to the tumor-selective killing of cancer cells by pharmacologically activated p53.