Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (48), p.41600-41615
• Main Authors: Zawacka-Pankau, Joanna, Grinkevich, Vera V., Hünten, Sabine, Nikulenkov, Fedor, Gluch, Angela, Li, Hai, Enge, Martin, Kel, Alexander, Selivanova, Galina
• Format: Article
• Language: English
• Subjects: c-Myc; Cancer Therapy; Cell Death; Glucose Metabolism; Glycolysis; Hypoxia-inducible Factor 1; Oncogene; p53; Tumor Metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.240812

Unique sensitivity of tumor cells to the inhibition of glycolysis is 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 transcription factors c-Myc and HIF1α, 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 down-regulation of HIF1α contributed to this effect. We identified Sp1 as a transcription 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 the “Achilles heel” of cancer cells (i.e. their dependence on glycolysis), which could contribute to the tumor-selective killing of cancer cells by pharmacologically activated p53. Background: High dependence of cancer cells on glycolysis is a good target for cancer therapy. Results: Tumor suppressor p53 represses the expression of key regulators of metabolic genes HIF1a and c-Myc and glucose transporters GLUT1 and GLUT12. Conclusion: Blocking ATP production network by pharmacologically activated p53 contributes to cancer cell death. Significance: Tumor-selective killing by reconstituted p53 might be in part due to inhibition of glycolysis.