Prolonged Cell Division Arrest Prevents Development of Cancers Caused by Epstein-Barr Virus

A mechanism has been identified that helps explain why despite most people having been infected with Epstein-Barr virus (EBV), very few develop the lymphomas and other cancers the virus can cause.

EBV was the first human tumor virus discovered. Although nearly all adults are infected with EBV, very few go on to develop disease, for reasons that are only now beginning to be understood.

Infection with EBV induces a period of very rapid cell division, which requires an increased supply of metabolites, such as nucleotides, amino acids, and lipids. Investigators at Duke University (Durham, NC, USA) found that EBV-infected cells that were unable to meet this increased metabolic demand were forced to stop proliferating and underwent a permanent growth arrest called senescence.

They reported in the January 22, 2016, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that arrested cells had a reduced level of mitochondrial respiration and a decrease in the expression of genes involved in the TCA (Kreb's) cycle and oxidative phosphorylation. Furthermore, the growth arrest in early infected cells could be rescued by supplementing the TCA cycle. Arrested cells were characterized by an increase in the expression of p53 pathway gene targets, including sestrins. Increased sestrin expression led to activation of AMPK (5' AMP-activated protein kinase), a reduction in mTOR (mammalian target of rapamycin) signaling, and, consequently, elevated autophagy that was important for cell survival.

In assessing the metabolic changes from early infection to long-term outgrowth, the investigators found concomitant increases in glucose import and surface glucose transporter 1 (GLUT1) levels, leading to elevated glycolysis, oxidative phosphorylation, and suppression of basal autophagy.

Senior author Dr. Micah Luftig, associate professor of molecular genetics and microbiology at Duke University, said, "For the most part, a healthy immune system stops Epstein-Barr virus from making much headway. In fact, many of the cancers linked to EBV are found mostly in immune-compromised patients whose ability to fight it off has been weakened. But another answer may be this newly discovered senescence trigger."

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