Hepatitis C Virus Alters Metabolism of Biogenic Polyamines by a ROS-dependent Induction of Key Enzymes of Their Metabolism

Abstract

Hepatitis C virus (HCV) infection often sets a chronic liver disease leading to fibrosis and hepatocellular carcinoma. These and other pathologies are induces by the virus by several mechanisms including pronounced oxidative stress and metabolic alterations. Though biogenic polyamines spermine and spermidine play pivotal role in liver functioning and even scavenging ROS, interplay between their metabolism and HCV infection has not been studied so far. Metabolism of spermine and spermidine is regulated mostly by three enzymes: ornithine decarboxylase (ODC) involved in their biosynthesis and by catabolic enzymes spermidine/spermine-N1-acetyl transferase (SSAT) and spermine oxidase (SMO). We have shown that chemically-induces oxidative stress triggers induction of ODC and SSAT via Nrf2 transcription factor. In lines with this, transient expression of two viral proteins, capsid and NS5A triggers a transient induction of both ODC and SSAT. In addition, both HCV core and NS5A induce sustained expression of spermine oxidase (SMO) in a ROS-independent fashion. Human hepatocarcinoma Huh7 cells harboring a full-length HCV replicon exhibited suppressed ODC and SSAT levels and elevated levels of SMO as well as depleted intracellular levels of spermine and spermidine. Noteworthy, SMO is a H2O2-producing enzyme implicated in development of gastric and colon cancer. Thus, role of HCV-induced SMO expression and of other alterations of polyamine metabolism in HCV replication and development of virus-associated liver pathologies should be explored in future.