Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Abstract

Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.human herpesvirus-8 | gamma-herpesvirus | latency | glycolysis

Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth

“…This host metabolic state shares similarities with the Warburg effect, where cancer cells switch to glycolysis to help meet their proliferative demands for nucleotides, amino acids, and lipids (Vander Heiden et al 2009). Interestingly, the Warburg effect has been observed in host cells infected by Kaposi's sarcoma herpesvirus, another obligate intracellular pathogen (Delgado et al 2010).…”

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…However, the in vivo relevance of these endothelial cell subtype-dependent findings requires further study (De Bock et al, 2013b;Parra-Bonilla et al, 2010). Interestingly, endothelial cells under pathological conditions exhibit characteristics of the Warburg effect -which is commonly associated with hyperproliferative cells -whereby glycolysis increases and oxidative phosphorylation decreases (Delgado et al, 2010;Fijalkowska et al, 2010;Metallo and Vander Heiden, 2013;Mullen and DeBerardinis, 2012). Upon activation by factors such as VEGF, endothelial cells increase expression of GLUT-1 as well as that of glycolytic enzymes, such as lactate dehydrogenase-A (LDH-A) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), among others (De Bock et al, 2013b;Parra-Bonilla et al, 2010;Peters et al, 2009;Yeh et al, 2008).…”

A viral kinase mimics S6 kinase to enhance cell proliferation

“…Glycolysis is a frequent bioenergetic adaptation of cancer cells, both in aerobic conditions and in hypoxic environments unfavorable for oxidative phosphorylation. Notably, vPK is induced by hypoxia (13,14), and, furthermore, KSHV is known to up-regulate glycolysis in both lytic and latent conditions (33,34). Thus, vPK may modulate the induction of the glycolytic phenotype.…”