Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc

Abstract

Unlike normal mammalian cells, which use oxygen to generate energy, cancer cells rely on glycolysis for energy and are therefore less dependent on oxygen. We previously observed that the c-Myc oncogenic transcription factor regulates lactate dehydrogenase A and induces lactate overproduction. We, therefore, sought to determine whether c-Myc controls other genes regulating glucose metabolism. In Rat1a fibroblasts and murine livers overexpressing c-Myc, the mRNA levels of the glucose transporter GLUT1, phosphoglucose isomerase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase were elevated. c-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.To form a three-dimensional multicellular spheroid mass, neoplastic cells alter their metabolism such that they are able to survive and grow in the hostile microenvironments created by the decreased blood flow found in tumor vasculature (1, 2). The most striking feature of tumor cells is the production of large amounts of lactic acid, which is due to the glycolytic conversion of glucose to lactic acid even in the presence of oxygen (3). This is often accompanied by an increased rate of glucose transport (4 -6).Glucose is a major regulator of gene transcription. In particular, it stimulates transcription of genes encoding glycolytic and lipogenic enzymes in adipocytes and hepatocytes through the carbohydrate response element (ChoRE), 1 a 5Ј-CACGTG-3Ј motif (7-11). The ChoRE is similar to the core binding site for the transcription factors USF2 (12), which is implicated in glucose metabolism, TFE3, and the hypoxia-inducible transcription factor (HIF). Hence, the ChoRE serves to integrate physiological signals through transcription factors to regulate glucose metabolism.During tumor formation, adaptation to hypoxia may be mediated by the HIF-1 family of transcription factors, which induce angiogenesis and other metabolic changes. (2,13,14). It is notable that glucose transport and transporter mRNA are induced in cells transformed by ras or src oncogenes (5). The c-myc oncogene is activated in a variety of pathways that are important in controlling cell growth and tumorigenesis. (15-18). Intriguingly, the ChoRE sequence matches the core E-box (5Ј-CACGTG-3Ј) binding site for c-Myc, which binds E-boxes of target genes to stimulate transcription (2,18,19). Previous work showed that c-Myc directly up-regulates the expression of the lactate dehydrogenase gene (LDH-A) (20), which is important in the transformed phenotype (anchorage-independent growth) of cells that overexpress c-Myc (20, 21). In addition to LDH-A, we report here the deregulation of GLUT 1 and several glycolytic genes by c-Myc. EXPERIME...

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

“…This reduction, in turn, may increase the intracellular pool of glucose-6-phosphate that can enter the glycolytic pathway. Our data indicate that loss of Ncoa2 is particularly protumorigenic in settings of MYC hyperactivity, which is consistent with the known ability of MYC to stimulate glycolytic metabolism potently through the direct induction of expression of numerous genes in the glycolytic pathway (53)(54)(55). Despite the potential relevance of this mechanism to tumorigenesis, we were unable to detect expression of G6Pase in the hepatoblast cells, suggesting that NCOA2 tumor-suppressor activity is independent of G6Pase in the hepatoblast system.…”

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

“…By using cells that are grown under normoxic conditions and the GEF-DN protein that specifically downregulates the Ras activation state, we show that metabolic rerouting does not take place in response to hypoxic conditions, but rather that it is a direct result of oncogenic activation of the Ras pathway. The transcription factor HIF1a, that is directly involved in the positive regulation of glycolytic enzymes in cooperation with Myc (Carmeliet et al, 1998;Osthus et al, 2000;Lee et al, 2004), may be involved in such a Ras-dependent regulation as its mRNA is upregulated in transformed cells (Supplementary Figure S3). While preferential use of the glycolytic pathway may give a selective advantage under hypoxic conditions, it does come at a price.…”

Metabolic reprogramming of the tumor

“…Conspicuous rates of glucose uptake in tumor cells result from the overexpression of glucose facilitative transporters, GLUTs (Pauwels et al, 2000). Augmented GLUT1 expression and translocation may arise through tumor-suppressor activity knockdown (Schwartzenberg-Bar-Yoseph et al, 2004) and/or oncogene over-activity (Flier et al, 1987;Osthus et al, 2000). This glucose torrent is canalized Figure 1 An overview of mammalian cell energy metabolism.…”