Peroxiredoxin IV plays a critical role in cancer cell growth and radioresistance through the activation of the Akt/GSK3 signaling pathways

Ding, Na; Jiang, Hong; Thapa, Pratik; Hao, Yanning; Alshahrani, Aziza; Allison, Derek B.; Izumi, Tohru; Liu, Xiaoqi; Wei, Qiou

doi:10.1016/j.jbc.2022.102123

Cited by 12 publications

(10 citation statements)

References 60 publications

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“…The genomic loss of exons in Prx4 was verified by genotyping using PCR with a combination of target-specific primers ( Figure 1 A). Using a previously validated anti-Prx4 and IHC staining method [ 9 , 17 ], we examined the expression of Prx4 in the mouse intestinal tract. We found that Prx4-positive staining was ubiquitously present in the mucosa, submucosa, and muscularis layers of mouse colon.…”

Section: Resultsmentioning

confidence: 99%

“…The tumors in transgenic groups also had lower oxidative stress and higher macrophage infiltration. Furthermore, Prx4 has been suggested to promote progression of prostate cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer [ 17 , 40 , 41 , 42 ]. Lastly, loss of Prx4 providing resistance to colitis fits the general trend observed when antioxidant enzymes are depleted in colitis models: loss of Prx1, Prx2, and Prx6 and the combined loss of GPx1 and catalase all improved colitis in mouse and rat models [ 43 , 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…A2228). The specificity of anti-Prx4 antibody was validated and verified using knockout cell lines and mouse tissues as previously reported [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

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Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

et al. 2023

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“…One possible mechanism for Prx4 upregulation is through androgen receptor signaling. Treatment of the LNCaP cell line with synthetic androgen R1881 led to a dose-dependent increase in Prx4 expression [ 101 ]. Depletion of Prx4 in LNCaP and DU145 cell lines decreased cell proliferation, migration and invasion, likely through decreased activation of Akt and GSK3 signaling pathways.…”

Section: Prx4 and Cancermentioning

confidence: 99%

“…Depletion of Prx4 in LNCaP and DU145 cell lines decreased cell proliferation, migration and invasion, likely through decreased activation of Akt and GSK3 signaling pathways. Prx4 depletion also sensitized the cancer cells to radiation in vitro and in mouse xenograft model [ 101 ]. Other Prxs, such as Prx1 also plays a role in prostate cancer development.…”

Section: Prx4 and Cancermentioning

confidence: 99%

Essential Roles of Peroxiredoxin IV in Inflammation and Cancer

et al. 2022

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Peroxiredoxin IV (Prx4) is a 2-Cysteine peroxidase with ubiquitous expression in human tissues. Prx4 scavenges hydrogen peroxide and participates in oxidative protein folding in the endoplasmic reticulum. In addition, Prx4 is secreted outside the cell. Prx4 is upregulated in several cancers and is a potential therapeutic target. We have summarized historical and recent advances in the structure, function and biological roles of Prx4, focusing on inflammatory diseases and cancer. Oxidative stress is known to activate pro-inflammatory pathways. Chronic inflammation is a risk factor for cancer development. Hence, redox enzymes such as Prx4 are important players in the crosstalk between inflammation and cancer. Understanding molecular mechanisms of regulation of Prx4 expression and associated signaling pathways in normal physiological and disease conditions should reveal new therapeutic strategies. Thus, although Prx4 is a promising therapeutic target for inflammatory diseases and cancer, further research needs to be conducted to bridge the gap to clinical application.

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New insights into the roles of peroxiredoxins in cancer

Ling

Wang

et al. 2023

Biomedicine & Pharmacotherapy

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Peroxiredoxin IV plays a critical role in cancer cell growth and radioresistance through the activation of the Akt/GSK3 signaling pathways

Cited by 12 publications

References 60 publications

Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

Essential Roles of Peroxiredoxin IV in Inflammation and Cancer

New insights into the roles of peroxiredoxins in cancer

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