FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction
Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy, and 5-Fluorouracil (5-FU) is the principal chemotherapeutic drug used for its treatment. However, 5-FU resistance remains a significant challenge. Under stress conditions, tumor metabolic reprogramming influences 5-FU r...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-02016-8 |
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| author | Zhukai Chen Jiacheng Xu Kang Fang Hanyu Jiang Zhuyun Leng Hao Wu Zehua Zhang Zeyu Wang Zhaoxing Li Mingchuang Sun Ziying Zhao Anqi Feng Shihan Zhang Yuan Chu Lechi Ye Meidong Xu Lingnan He Tao Chen |
| author_facet | Zhukai Chen Jiacheng Xu Kang Fang Hanyu Jiang Zhuyun Leng Hao Wu Zehua Zhang Zeyu Wang Zhaoxing Li Mingchuang Sun Ziying Zhao Anqi Feng Shihan Zhang Yuan Chu Lechi Ye Meidong Xu Lingnan He Tao Chen |
| author_sort | Zhukai Chen |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy, and 5-Fluorouracil (5-FU) is the principal chemotherapeutic drug used for its treatment. However, 5-FU resistance remains a significant challenge. Under stress conditions, tumor metabolic reprogramming influences 5-FU resistance. Serine metabolism plasticity is one of the crucial metabolic pathways influencing 5-FU resistance in CRC. However, the mechanisms by which CRC modulates serine metabolic reprogramming under serine-deprived conditions remain unknown. We found that exogenous serine deprivation enhanced the expression of serine synthesis pathway (SSP) genes, which in turn supported CRC cell growth and 5-FU resistance. Serine deprivation activate the ERK1/2-p-ELK1 signaling axis, leading to upregulated FOXC1 expression in CRC cells. Elevated FOXC1 emerged as a critical element, promoting the transcription of serine metabolism enzymes PHGDH, PSAT1, and PSPH, which in turn facilitated serine production, supporting CRC growth. Furthermore, through serine metabolism, FOXC1 influenced purine metabolism and DNA damage repair, thereby increasing 5-FU resistance. Consequently, combining dietary serine restriction with targeted therapy against the ERK1/2-pELK1-FOXC1 axis could be a highly effective strategy for treating CRC, enhancing the efficacy of 5-FU. |
| format | Article |
| id | doaj-art-c141348309314b6d8e753bbef390cd53 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-c141348309314b6d8e753bbef390cd532025-01-12T12:32:54ZengBMCCell Communication and Signaling1478-811X2025-01-0123112010.1186/s12964-024-02016-8FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restrictionZhukai Chen0Jiacheng Xu1Kang Fang2Hanyu Jiang3Zhuyun Leng4Hao Wu5Zehua Zhang6Zeyu Wang7Zhaoxing Li8Mingchuang Sun9Ziying Zhao10Anqi Feng11Shihan Zhang12Yuan Chu13Lechi Ye14Meidong Xu15Lingnan He16Tao Chen17Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityDepartment of Colorectal Surgery, Zhongshan Hospital, Fudan UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityEndoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji UniversityAbstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy, and 5-Fluorouracil (5-FU) is the principal chemotherapeutic drug used for its treatment. However, 5-FU resistance remains a significant challenge. Under stress conditions, tumor metabolic reprogramming influences 5-FU resistance. Serine metabolism plasticity is one of the crucial metabolic pathways influencing 5-FU resistance in CRC. However, the mechanisms by which CRC modulates serine metabolic reprogramming under serine-deprived conditions remain unknown. We found that exogenous serine deprivation enhanced the expression of serine synthesis pathway (SSP) genes, which in turn supported CRC cell growth and 5-FU resistance. Serine deprivation activate the ERK1/2-p-ELK1 signaling axis, leading to upregulated FOXC1 expression in CRC cells. Elevated FOXC1 emerged as a critical element, promoting the transcription of serine metabolism enzymes PHGDH, PSAT1, and PSPH, which in turn facilitated serine production, supporting CRC growth. Furthermore, through serine metabolism, FOXC1 influenced purine metabolism and DNA damage repair, thereby increasing 5-FU resistance. Consequently, combining dietary serine restriction with targeted therapy against the ERK1/2-pELK1-FOXC1 axis could be a highly effective strategy for treating CRC, enhancing the efficacy of 5-FU.https://doi.org/10.1186/s12964-024-02016-8Colorectal cancer5-Fluorouracil resistanceDe novo serine synthesisFOXC1Metabolic reprogramming |
| spellingShingle | Zhukai Chen Jiacheng Xu Kang Fang Hanyu Jiang Zhuyun Leng Hao Wu Zehua Zhang Zeyu Wang Zhaoxing Li Mingchuang Sun Ziying Zhao Anqi Feng Shihan Zhang Yuan Chu Lechi Ye Meidong Xu Lingnan He Tao Chen FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction Cell Communication and Signaling Colorectal cancer 5-Fluorouracil resistance De novo serine synthesis FOXC1 Metabolic reprogramming |
| title | FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction |
| title_full | FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction |
| title_fullStr | FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction |
| title_full_unstemmed | FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction |
| title_short | FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction |
| title_sort | foxc1 mediated serine metabolism reprogramming enhances colorectal cancer growth and 5 fu resistance under serine restriction |
| topic | Colorectal cancer 5-Fluorouracil resistance De novo serine synthesis FOXC1 Metabolic reprogramming |
| url | https://doi.org/10.1186/s12964-024-02016-8 |
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