Loss of Peroxiredoxin IV Renders Mice Resistant to Chemically Induced Colon Carcinogenesis

Abstract

Oxidative stress is an important contributing factor in many types of human disease including cancer. One of the major antioxidants involved in the maintenance of cellular redox balance is the Peroxiredoxin (Prx) family of proteins. They carry out such function through scavenging and reducing hydrogen peroxide, alkyl hydroperoxides and peroxynitrite with high sensitivity. Peroxiredoxin IV (Prx4) is one of the six members of the Prx family and is highly conserved in prokaryotes and eukaryotes. In human genome, Prx4 gene is located in the X chromosome (Xp22.11). Prx4 protein is mainly localized in the Endoplasmic Reticulum (ER) where it plays an important role in ROS scavenging as well as oxidative protein folding. It is also present in the cytoplasm and can be secreted into extracellular space under physiological conditions. Sulfiredoxin (Srx) is another enzyme that protects cells against oxidative stress by reducing hyperoxidized 2-cysteine-containing Prxs. Prx4 has been found to be overexpressed in a number of human cancers including colorectal cancer. Previously, we have discovered that reduced expression of Srx disrupts chemically induced colorectal cancer development in mice. However, the role of Prx4 in colon carcinogenesis has not been studied before. In this study, Prx4 null mice and Srx-Prx4 null mice were generated in pure FVB/N background. Mouse colon carcinogenesis was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Briefly, wildtype, Prx4 null mice and Srx-Prx4 null mice at 8-week of age were injected intraperitoneally with 10mg/kg of AOM in week 1. Mice were administered with two rounds of 2% DSS in drinking water in weeks 2 and 10. Twenty weeks after AOM injection, all mice were euthanized and examined for tumors. Our results indicate that Prx4 null mice have significantly reduced tumor multiplicity as well as smaller tumor size. This suggests that Prx4 has a critical oncogenic role in cancer development. We are currently conducting mechanistic studies to determine how the loss of Prx4 leads to mice resistant to colon carcinogenesis in the AOM/DSS model.