Regulation of Cellular Metabolism by High-Risk Human Papillomaviruses

Abstract

The alteration of glucose metabolism is one of the first biochemical characteristics associated with cancer cells since most of these cells increase glucose consumption and glycolytic rates even in the presence of oxygen, which has been called “aerobic glycolysis” or the Warburg effect. Human papillomavirus (HPV) is associated with approximately 5% of all human cancers worldwide, principally to cervical cancer. E6 and E7 are the main viral oncoproteins which are required to preserve the malignant phenotype. These viral proteins regulate the cell cycle through their interaction with tumor suppressor proteins p53 and pRB, respectively. Together with the viral proteins E5 and E2, E6 and E7 can favor the Warburg effect and contribute to radio- and chemoresistance through the increase in the activity of glycolytic enzymes, as well as the inhibition of the Krebs cycle and the respiratory chain. These processes lead to a fast production of ATP obtained by Warburg, which could help satisfy the high energy demands of cancer cells during proliferation. In this way HPV proteins could promote cancer hallmarks. However, it is also possible that during an early HPV infection, the Warburg effect could help in the achievement of an efficient viral replication.

Keywords: Warburg effect; human papillomavirus; metabolism; oxidative phosphorylation.

Figure 1

ATP production from food metabolism. Amino acids, monosaccharides, and fatty acids are produced from the metabolism of proteins, carbohydrates, and fats, respectively, from which pyruvate and/or acetyl-CoA are obtained, which, in turn, are generally metabolized in the Krebs cycle and the oxidative phosphorylation system.

Figure 2

Metabolism of glucose in normal and cancer cells. The glucose (Glu) that enters the cell is phosphorylated to glucose 6 phosphate (Glu 6P) and, subsequently, is metabolized to pyruvate (a,b). In normal cells, pyruvate is metabolized to acetyl-coenzyme A (Acetyl-CoA) and continues its metabolism in the Krebs cycle (KC) and the oxidative phosphorylation (OXPHOS) system (a). In cancer cells, glucose entry is increased, and pyruvate is metabolized to lactate, which is then expelled from the cells (b). The Krebs cycle can be fed by intermediaries from glutaminolysis.

Figure 3

Modulation of the Warburg effect by HPV oncoproteins. E6, E7, and E5 viral proteins activate the glycolytic pathway (arrows). E6 with E6 associated protein (E6AP) inhibits repressors of the glycolytic pathway such as p53, which activates the TP53 induced glycolysis and apoptosis regulator (TIGAR), a glycolytic repressor protein (truncated arrow). TIGAR activates cytochrome c oxidase assembly protein (SCO2), activator of oxidative phosphorylation (OXPHOS). Hence, the absence of p53 promotes glycolysis. E5 activates epidermal grow factor receptor (EGFR) pathways; E6 activates Pyruvate kinase isoform 2 (PKM2), PI3K/AKT and rapamycin complex 1 (mTOR); E6 and E7 activate hypoxia-inducible factor (HIF1. Glu: glucose). The HPV type is indicated.

Figure 4

The modulation of glucose metabolism by HPV oncoproteins favor glycolysis instead of OXPHOS. HR-HPV E6 oncoproteins promote glucose uptake through the overexpression of glucose transporters GLUT and SGLT. Both E6 and E7 oncoproteins induce the expression of hexokinase, enzyme associated to the first step of glucose metabolism. Moreover, E6 can promote nucleotide synthesis through the degradation of p53, which is an antagonist of glucose 6-P-dehidrogenase, a key enzyme in the pentose phosphate pathway (PPP). The glycolytic pathway is carried out in two phases. First, in the preparatory or glucose activation phase, a six-carbon glucose molecule breaks down into two molecules with three carbons each: one glyceraldehyde-3-phosphate and the other is dihydroxyacetone phosphate, which is transformed into glyceraldehyde-3-phosphate. In these reactions, two molecules of ATP are consumed. Second, the energy extraction phase, involves the conversion of the two glyceraldehyde-3-phosphate molecules into two pyruvate molecules by pyruvate kinase, which is activated by E6 and E7 oncoproteins. This process results in the production of four ATP molecules through substrate-level phosphorylation. Pyruvate is metabolized to acetyl-CoA by pyruvate dehydrogenase, which, in turn, is negatively regulated by pyruvate dehydrogenase kinase 2 (PDK2). PDK2 is activated in the absence of p53, a process induced by E6, avoiding acetyl-CoA production. Moreover, p53 degradation avoids glutaminase 2 (GLS2) activation and glutaminolysis, which in turn decreases α-ketoglutarate levels. Thus, E6 does not permit an optimal function of the Krebs cycle, inducing lactate production by lactate dehydrogenase. E6 prevents the expression of miRNA34a and lactate dehydrogenase deactivation. HPV type is indicated. T arrows indicate inhibition. Black line arrows and thick blue arrows indicate the direction of the reaction.

Figure 5

Modulation of the oxidative phosphorylation system by HPV18 E2 protein. Electrons are transferred from NADH or FADH₂ to O₂ using a series of electron carriers: Complex I, II, III, IV, and V favor the translocation of protons and generate an electrochemical gradient of protons in the intermembrane space. Red arrows show the electron flux. Electrons (e⁻); protons (H⁺); oxygen (O₂); water (H₂O); coenzyme Q (CoQ), and cytochrome C (Cyt C). Since E2 modifies the mitochondrial cristae morphology, releasing ROS, it could possibly modulate Complex III, which is a mediator of mitochondrial ROS production; and it could also modulate Complex V, which is a regulator of the mitochondrial cristae structure. The question mark (?) indicates the possible effect of E2 on the complexes III and V.