Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development
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 includin...
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MDPI AG
2023-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/3/677 |
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| author | Pratik Thapa Hong Jiang Na Ding Yanning Hao Aziza Alshahrani Eun Y. Lee Junichi Fujii Qiou Wei |
| author_facet | Pratik Thapa Hong Jiang Na Ding Yanning Hao Aziza Alshahrani Eun Y. Lee Junichi Fujii Qiou Wei |
| author_sort | Pratik Thapa |
| collection | DOAJ |
| description | 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<sup>−/−</sup> mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4<sup>−/−</sup> 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. |
| first_indexed | 2024-03-11T07:00:30Z |
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| id | doaj.art-5f56db4d9e34476c8654c39ef27be1bc |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T07:00:30Z |
| publishDate | 2023-03-01 |
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| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-5f56db4d9e34476c8654c39ef27be1bc2023-11-17T09:18:13ZengMDPI AGAntioxidants2076-39212023-03-0112367710.3390/antiox12030677Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer DevelopmentPratik Thapa0Hong Jiang1Na Ding2Yanning Hao3Aziza Alshahrani4Eun Y. Lee5Junichi Fujii6Qiou Wei7Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USADepartment of Biomolecular Function, Yamagata University, Yamagata 990-9585, JapanDepartment of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40506, USAPeroxiredoxin 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<sup>−/−</sup> mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4<sup>−/−</sup> 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.https://www.mdpi.com/2076-3921/12/3/677peroxiredoxinsulfiredoxincolorectal cancerredoxoxidative stresstumorigenesis |
| spellingShingle | Pratik Thapa Hong Jiang Na Ding Yanning Hao Aziza Alshahrani Eun Y. Lee Junichi Fujii Qiou Wei Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development Antioxidants peroxiredoxin sulfiredoxin colorectal cancer redox oxidative stress tumorigenesis |
| title | Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development |
| title_full | Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development |
| title_fullStr | Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development |
| title_full_unstemmed | Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development |
| title_short | Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development |
| title_sort | loss of peroxiredoxin iv protects mice from azoxymethane dextran sulfate sodium induced colorectal cancer development |
| topic | peroxiredoxin sulfiredoxin colorectal cancer redox oxidative stress tumorigenesis |
| url | https://www.mdpi.com/2076-3921/12/3/677 |
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