Abstract
Peroxiredoxin IV (Prx4), a typical two-cysteine-containing member of the peroxidase family, functions as an antioxidant to maintain cellular redox homeostasis through the reduction of reactive oxygen species (ROS) via cycles of oxidation–reduction reactions. Under oxidative stress, all Prxs including Prx4 are inactivated as their catalytic cysteines undergo hyperoxidation, and hyperoxidized two-cysteine Prxs can be exclusively repaired and revitalized through the reduction cycle catalyzed by sulfiredoxin (Srx). Previously, we showed that Prx4 is a preferred substrate of Srx, and knockout of Srx in mice leads to resistance to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis. To further understand the significance of the Srx/Prx4 axis in colorectal cancer development, Prx4−/− mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4−/− genotype had significantly fewer and smaller tumors. Histopathological analysis revealed that loss of Prx4 leads to increased cell death through lipid peroxidation and lower infiltration of inflammatory cells in the knockout tumors compared to wildtype. Treatment with DSS alone also showed decreased infiltration of macrophages and lymphocytes in the colon of knockout mice, suggesting a role for Prx4 in inflammatory response. In addition, loss of Prx4 caused alterations in plasma cytokines and chemokines after DSS and AOM/DSS treatments. These findings suggest that loss of Prx4 protects mice from AOM/DSS- induced colon tumorigenesis. Thus, targeting Prx4 may provide novel strategies for colon cancer prevention and treatment.
Document Type
Article
Publication Date
3-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/antiox12030677
Funding Information
This research was funded by the National Institutes of Health (NCI R01CA222596, NIEHS T32ES07266), Department of Defense (grant number W81XWH-16-1-0203), American Cancer Society (grant number RSG-16-213-01-TBE), and Kentucky Lung Cancer Research Program (KLCRP2016). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies.
Repository Citation
Thapa, Pratik; Jiang, Hong; Ding, Na; Hao, Yanning; Alshahrani, Aziza; Lee, Eun Young; Fujii, Junichi; and Wei, Qiou, "Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development" (2023). Markey Cancer Center Faculty Publications. 360.
https://uknowledge.uky.edu/markey_facpub/360
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Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).