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Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.

ABSTRACT: Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism and sufficient to promote enhanced glycolysis in cultured epithelial cells by activation of MYC. E4ORF1 localizes to the nucleus, binds to MYC, and enhances MYC binding to glycolytic target genes, resulting in elevated expression of specific glycolytic enzymes. E4ORF1 activation of MYC promotes increased nucleotide biosynthesis from glucose intermediates and enables optimal adenovirus replication in primary lung epithelial cells. Our findings show how a viral protein exploits host cell machinery to reprogram cellular metabolism and promote optimal progeny virion generation.

SUBMITTER: Thai M

PROVIDER: S-EPMC4294542 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.

Thai Minh M Graham Nicholas A NA Braas Daniel D Nehil Michael M Komisopoulou Evangelia E Kurdistani Siavash K SK McCormick Frank F Graeber Thomas G TG Christofk Heather R HR

Cell metabolism 20140401 4

Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism a ...[more]

PMID: 24703700

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Project description:Background Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. Methods We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. Results We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. Conclusions P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-023-03985-z.

Project description:BackgroundLight at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells.MethodsMale Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet.ResultsWe found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions.ConclusionsData indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.

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Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.

Publications

Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.

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