Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer
Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found ne...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/16001 |
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| author | Wenyuan Zhu Siqi Yang Delan Meng Qingsong Wang Jianguo Ji |
| author_facet | Wenyuan Zhu Siqi Yang Delan Meng Qingsong Wang Jianguo Ji |
| author_sort | Wenyuan Zhu |
| collection | DOAJ |
| description | Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found neutrophils from CRC patients have enhanced NETs formation capacity and increased NETs positively correlate with CRC progression. By quantitative proteomic analysis of clinical samples and cell lines, we found that decreased secreted protein acidic and rich in cysteine (SPARC) results in massive NETs formation and integrin α5β1 is the hub protein of NETs-tumor cell interaction. Mechanistically, SPARC regulates the activation of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) pathway by interacting with the receptor for activated C kinase 1 (RACK1). Over-activated NADPH oxidase generates more reactive oxygen species (ROS), leading to the release of NETs. Then, NETs upregulate the expression of integrin α5β1 in tumor cells, which enhances adhesion and activates the downstream signaling pathways to promote proliferation and migration. The combination of NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and integrin α5β1 inhibitor ATN-161 (Ac-PHSCN-NH2) effectively suppresses tumor progression in vivo. Our work reveals the mechanistic link between NETs and tumor progression and suggests a combination therapy against NETs-mediated metastasis for CRC. |
| first_indexed | 2024-03-11T11:27:11Z |
| format | Article |
| id | doaj.art-453e5f46944c4ca1b939e782f17544ab |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:27:11Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-453e5f46944c4ca1b939e782f17544ab2023-11-10T15:06:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124211600110.3390/ijms242116001Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal CancerWenyuan Zhu0Siqi Yang1Delan Meng2Qingsong Wang3Jianguo Ji4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, ChinaState Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, ChinaState Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, ChinaState Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, ChinaState Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, ChinaMetastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found neutrophils from CRC patients have enhanced NETs formation capacity and increased NETs positively correlate with CRC progression. By quantitative proteomic analysis of clinical samples and cell lines, we found that decreased secreted protein acidic and rich in cysteine (SPARC) results in massive NETs formation and integrin α5β1 is the hub protein of NETs-tumor cell interaction. Mechanistically, SPARC regulates the activation of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) pathway by interacting with the receptor for activated C kinase 1 (RACK1). Over-activated NADPH oxidase generates more reactive oxygen species (ROS), leading to the release of NETs. Then, NETs upregulate the expression of integrin α5β1 in tumor cells, which enhances adhesion and activates the downstream signaling pathways to promote proliferation and migration. The combination of NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and integrin α5β1 inhibitor ATN-161 (Ac-PHSCN-NH2) effectively suppresses tumor progression in vivo. Our work reveals the mechanistic link between NETs and tumor progression and suggests a combination therapy against NETs-mediated metastasis for CRC.https://www.mdpi.com/1422-0067/24/21/16001colorectal cancermetastasisneutrophil extracellular trapsquantitative proteomicscombination therapy |
| spellingShingle | Wenyuan Zhu Siqi Yang Delan Meng Qingsong Wang Jianguo Ji Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer International Journal of Molecular Sciences colorectal cancer metastasis neutrophil extracellular traps quantitative proteomics combination therapy |
| title | Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer |
| title_full | Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer |
| title_fullStr | Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer |
| title_full_unstemmed | Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer |
| title_short | Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer |
| title_sort | targeting nadph oxidase and integrin α5β1 to inhibit neutrophil extracellular traps mediated metastasis in colorectal cancer |
| topic | colorectal cancer metastasis neutrophil extracellular traps quantitative proteomics combination therapy |
| url | https://www.mdpi.com/1422-0067/24/21/16001 |
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