Oncogenic viruses and tumor glucose metabolism: like kids in a candy store

Abstract

Oncogenic viruses represent a significant public health burden in light of the multitude of malignancies that result from chronic or spontaneous viral infection and transformation. Although many of the molecular signaling pathways that underlie virus-mediated cellular transformation are known, the impact of these viruses on metabolic signaling and phenotype within proliferating tumor cells is less well understood. Whether the interaction of oncogenic viruses with metabolic signaling pathways involves enhanced glucose uptake and glycolysis (both hallmark features of transformed cells) or dysregulation of molecular pathways that regulate oxidative stress, viruses are adept at facilitating tumor expansion. Through their effects on cell proliferation pathways, such as the PI3K and MAPK pathways, the cell cycle regulatory proteins p53 and ATM, and the cell stress response proteins HIF-1α and AMPK, viruses exert control over critical metabolic signaling cascades. Additionally, oncogenic viruses modulate the tumor metabolomic profile through direct and indirect interactions with glucose transporters, such as GLUT1, and specific glycolytic enzymes, including pyruvate kinase, glucose 6-phosphate dehydrogenase, and hexokinase. Through these pathways, oncogenic viruses alter the phenotypic characteristics and energy-use methods of transformed cells; therefore, it may be possible to develop novel antiglycolytic therapies to target these dysregulated pathways in virus-derived malignancies.

Figure 1. Oncogenic viruses exert metabolic control through the regulation of cellular growth, cell cycle, and cell stress signals

Oncogenic viruses, including Hepatitis C Virus (HCV), Epstein-Barr Virus (EBV), and polyoma viruses, induce cellular proliferation through the PI3K and MAPK pathways and inhibit cell cycle arrest and DNA damage responses through inhibition of p53 and ATM. On the other hand, these viruses induce hypoxia-inducible factor-1α (HIF-1α) expression as well as AMP-activated protein kinase (AMPK)-dependent signaling. As a result, these pathways activate oxidative stress, glucose transport, and glycolytic metabolism.

Figure 2

Oncogenic viruses regulate glucose uptake and glycolytic flux in transformed cells Glucose uptake processes are enhanced by Rous sarcoma virus (RSV), and Epstein-Barr Virus (EBV) induces trafficking of the GLUT1 transporter to the plasma membrane. HTLV-1 utilizes the GLUT1 transporter to enter and infect cells, where it may then induce subsequent tumor formation. RSV enhances the activities of key glycolytic enzymes, including hexokinase (HK), glucose 6-phosphate dehydrogenase (G6PDH), and phosphofructokinase-1 (PFK-1), all of which contribute to enhanced glycolytic ATP production. SV40 enhances transaldolase (TALDO) activity, providing nucleotide precursors and sufficient NADPH reducing equivalents for cellular demands. The M2 isoform of pyruvate kinase (M2PK) is affected by multiple viruses, such as HPV, RSV, and HCV, which activate and induce changes in M2PK structure. In addition, HCV enhances lactate production while inhibiting mitochondrial oxidative phosphorylation, thus promoting glycolytic flux.