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...
Expression of the forkhead transcription factor FoxM1 correlates with proliferative status in a variety of normal and transformed cell types. Elevated expression of FoxM1 has been noted in both hepatocellular carcinoma and basal cell carcinoma. However, whether FoxM1 expression is essential for the viability of transformed cells is unknown. We report here that the expression of FoxM1 is significantly elevated in primary breast cancer. Microarray analysis shows that FoxM1 regulates genes that are essential for faithful chromosome segregation and mitosis, including Nek2, KIF20A, and CENP-A. Loss of FoxM1 expression generates mitotic spindle defects, delays cells in mitosis, and induces mitotic catastrophe. Timelapse microscopy indicates that depletion of FoxM1 generates cells that enter mitosis but are unable to complete cell division, resulting in either mitotic catastrophe or endoreduplication. These findings indicate that FoxM1 depletion causes cell death due to mitotic catastrophe and that inhibiting FoxM1 represents a therapeutic strategy to target breast cancer. (Cancer Res 2005; 65(12): 5181-9)
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