Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer
Abstract Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulat...
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Nature Portfolio
2024-02-01
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| Online Access: | https://doi.org/10.1038/s41598-024-55544-1 |
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| author | Liangming Zhang Xiongfeng Chen Jianwei Wang Meihong Chen Juan Chen Wanzhen Zhuang Yu Xia Zhixin Huang Yue Zheng Yi Huang |
| author_facet | Liangming Zhang Xiongfeng Chen Jianwei Wang Meihong Chen Juan Chen Wanzhen Zhuang Yu Xia Zhixin Huang Yue Zheng Yi Huang |
| author_sort | Liangming Zhang |
| collection | DOAJ |
| description | Abstract Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment. |
| first_indexed | 2024-03-07T15:05:22Z |
| format | Article |
| id | doaj.art-77e5bc931213410190d160d2d1321dab |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:05:22Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-77e5bc931213410190d160d2d1321dab2024-03-05T18:55:01ZengNature PortfolioScientific Reports2045-23222024-02-0114111610.1038/s41598-024-55544-1Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancerLiangming Zhang0Xiongfeng Chen1Jianwei Wang2Meihong Chen3Juan Chen4Wanzhen Zhuang5Yu Xia6Zhixin Huang7Yue Zheng8Yi Huang9Shengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityDepartment of Clinical Laboratory, Fujian Provincial HospitalDepartment of Clinical Laboratory, Fujian Provincial HospitalShengli Clinical Medical College, Fujian Medical UniversityShengli Clinical Medical College, Fujian Medical UniversityAbstract Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.https://doi.org/10.1038/s41598-024-55544-1CST1Esophageal squamous cell carcinomaOxidative phosphorylationMEK/ERK pathway |
| spellingShingle | Liangming Zhang Xiongfeng Chen Jianwei Wang Meihong Chen Juan Chen Wanzhen Zhuang Yu Xia Zhixin Huang Yue Zheng Yi Huang Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer Scientific Reports CST1 Esophageal squamous cell carcinoma Oxidative phosphorylation MEK/ERK pathway |
| title | Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer |
| title_full | Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer |
| title_fullStr | Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer |
| title_full_unstemmed | Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer |
| title_short | Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer |
| title_sort | cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation mek erk axis in esophageal squamous carcinoma cancer |
| topic | CST1 Esophageal squamous cell carcinoma Oxidative phosphorylation MEK/ERK pathway |
| url | https://doi.org/10.1038/s41598-024-55544-1 |
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