Abstract
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.
Highlights
High dependence of cancer cells on glycolysis is a good target for cancer therapy
RITA Inhibits Metabolism of Cancer Cell in a p53-dependent Manner—We addressed the question of whether reactivated p53 can mediate the inhibition of aerobic glycolysis, the key ATP-generating pathway in cancer cells
Assessment of p53 Binding to Metabolic Genes Using ChIPseq—In order to assess whether p53 might play a direct role in regulation of expression of a set of metabolic genes, we investigated whether p53 binds the promoter regions of these genes in cellulo by analyzing p53 genome-wide chromatin occupancy upon 1 M RITA treatment in MCF7 cells using chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq). 6 million sequencing reads were mapped to the human genome (NCBI36) and used to calculate the height of the peaks
Summary
Results: Tumor suppressor p53 represses the expression of key regulators of metabolic genes HIF1a and c-Myc and glucose transporters GLUT1 and GLUT12. Key glycolytic enzymes acting downstream of hexokinase include PFKFB3, PFK1, pyruvate dehydrogenase (PDH), and pyruvate dehydrogenase kinase (PDK) (Fig. 2C) The oncogenic networks, such as PI3K/Akt, c-Myc, and HIF1 influence the metabolic shift during cancerogenesis and support growth and proliferation of cancer cells under metabolic stress and hypoxia. P53-mediated Inhibition of Glycolysis to Fight Cancer p53 is a transcription factor that suppresses tumor development by regulating the expression of genes inducing cell cycle arrest, apoptosis, and senescence upon stress conditions [14]. We report a potent p53-dependent inhibition of the glucose transport and the first steps of glycolysis via the transcriptional repression of key players of these processes
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