Nrf2-activated expression of sulfiredoxin contributes to urethane-induced lung tumorigenesis

Abstract

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking and exposure to chemical carcinogens are among the risk factors of lung tumorigenesis. In this study, we found that cigarette smoke condensate and urethane significantly stimulated the expression of sulfiredoxin (Srx) at the transcript and protein levels in cultured normal lung epithelial cells, and such stimulation was mediated through the activation of nuclear related factor 2 (Nrf2). To study the role of Srx in lung cancer development in vivo, mice with Srx wildtype, heterozygous or knockout genotype were subjected to the same protocol of urethane treatment to induce lung tumors. By comparing tumor multiplicity and volume between groups of mice with different genotype, we found that Srx knockout mice had a significantly lower number and smaller size of lung tumors. Mechanistically, we demonstrated that loss of Srx led to a decrease of tumor cell proliferation as well as an increase of tumor cell apoptosis. These data suggest that Srx may have an oncogenic role that contributes to the development of lung cancer in smokers or urethane-exposed human subjects.

Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer

“…There are few in vivo studies that showed EnAOs promoting tumor initiation. Srx −/− mice exhibited few smaller urethane-induced lung tumors and DMBA/TPA-induced skin tumors [ 90 , 91 ]. Some investigations on one hand suggest evidence for EnAOs preventing cancer initiation, whereas on the other hand, some studies suggest that EnAOs promote tumor initiation.…”

Antioxidant Gene Signature Impacts the Immune Infiltration and Predicts the Prognosis of Kidney Renal Clear Cell Carcinoma

“…Cancer cells actively upregulate a variety of antioxidant systems to buffer the level of ROS, so that ROS in the tumor cells reach a new balance, which is limited to a range that is conducive to promoting tumor progression (Moloney and Cotter, 2018). Although some previous studies have proven that certain antioxidants can prevent cancer (Sakumi et al, 2003;McLoughlin and Orlicky, 2019), other studies have shown that tumors can also occur in similar situation (Müller et al, 2013;Mishra et al, 2018). These results indicate that antioxidants and ROS are closely correlated with the development of cancer, and further research is required to analyze these seemingly contradictory findings.…”

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila

“…On the other hand, by reducing ROS and affecting apoptosis, Srx may favor the survival of cancerous cells and thereby contribute to carcinogenesis [ 48 ]. For instance, Srx underexpression can sensitize cancer cells to ER stress-induced cell death [ 49 ], increase apoptosis of tumor cells and thus decrease tumor cell proliferation, while the opposite effects have been observed in Srx overexpressors, which correlated with more aggressive cancers and poor prognosis [ 8 , 48 , 50 , 51 , 52 , 53 ].…”