Human Papillomavirus Types 16 and 18 Early-expressed Proteins Differentially Modulate the Cellular Redox State and DNA Damage

Abstract

Oxidative stress has been proposed as a risk factor for cervical cancer development. However, few studies have evaluated the redox state associated with human papillomavirus (HPV) infection. The aim of this work was to determine the role of the early expressed viral proteins E1, E2, E6 and E7 from HPV types 16 and 18 in the modulation of the redox state in an integral form. Therefore, generation of reactive oxygen species (ROS), concentration of reduced glutathione (GSH), levels and activity of the antioxidant enzymes catalase and superoxide dismutase (SOD) and deoxyribonucleic acid (DNA) damage, were analysed in epithelial cells ectopically expressing the viral proteins. Our research shows that E6 oncoproteins decreased GSH and catalase protein levels, as well as its enzymatic activity, which was associated with an increase in ROS production and DNA damage. In contrast, E7 oncoproteins increased GSH, as well as catalase protein levels and its activity, which correlated with a decrease in ROS without affecting DNA integrity. The co-expression of both E6 and E7 oncoproteins neutralized the effects that were independently observed for each of the viral proteins. Additionally, the combined expression of E1 and E2 proteins increased ROS levels with the subsequent increase in the marker for DNA damage phospho-histone 2AX (γH2AX). A decrease in GSH, as well as SOD2 levels and activity were also detected in the presence of E1 and E2, even though catalase activity increased. This study demonstrates that HPV early expressed proteins differentially modulate cellular redox state and DNA damage.

Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state

“…In contrast, Cruz-Gregorio and co-workers demonstrated that expression of HR-HPVs E6/E7 does not alter ROS production or catalase activation in C33A cells. (35) Taken together, the observations described above reveal the existence of variable effects of the HPV oncogenes on the expression and/or activity of catalase in different cell systems. Further studies are needed to understand the impact of oncogenes from different HPV types on this important cellular protein and to determine the role of catalase in HPV-mediated pathologies.…”

“…4, HaCaT cells containing HPV-18 E5/E6/E7 viral oncogenes exhibited significantly higher levels of oxidised CM-H2DCF probe (CM-DCF) compared to that observed in HaCaT control cells, HaCaT E5 cells, and HaCaT E6/E7 cells, indicating an increase in intracellular ROS. As it has been previously observed that the E6 oncoprotein of HPV-18 enhances ROS production and decreases catalase activity, (35) we questioned if this increment in intracellular ROS in HaCaT cells cotransduced with the three oncogenes could be due to a reduction in the function of the cell antioxidant systems. To assess this, we analysed GSH and catalase levels and their enzymatic activity, and we determined the protein levels of peroxiredoxin 1 (PRX1).…”

Regulation of Cellular Metabolism by High-Risk Human Papillomaviruses

“…Cells have a battery of antioxidants, such as glutathione (GSH), superoxide dismutase (SOD) 1, 2 and 3, catalase (CAT), peroxidases (Prxs), and thioredoxins (Trxs), among others, which respond quickly and efficiently against OS [ 98 ]. It has been shown that the co-expression of E2 and E1 from HPV18 decreases GSH levels and SOD1 and 2 activity inducing an increase in ROS levels and DNA damage [ 99 ].…”

Oxidative stress: therapeutic approaches for cervical cancer treatment

“…Temozolomide (TMZ)-resistant glioma cells showed low levels of ROS and high GSH and glutathione reductase levels, exhibiting greater antioxidant capacity than sensitive cells, suggesting that this redox system may be an important therapeutic target 158 . Interestingly, HPV proteins can also modulate ROS by regulating GSH and SOD levels 159 . In fact, a relationship between GSH levels in cervical cancer cells and resistance to doxorubicin treatment, an anticancer drug that induces DNA damage and ROS production, was observed 160 .…”