Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase
Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remains unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-e...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825001616 |
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| author | Oladimeji Aladelokun Katherine Benitez Yuying Wang Abhishek Jain Domenica Berardi Georgio Maroun Xinyi Shen Jatin Roper Joanna Gibson Kaelyn Sumigray Sajid A. Khan Caroline H. Johnson |
| author_facet | Oladimeji Aladelokun Katherine Benitez Yuying Wang Abhishek Jain Domenica Berardi Georgio Maroun Xinyi Shen Jatin Roper Joanna Gibson Kaelyn Sumigray Sajid A. Khan Caroline H. Johnson |
| author_sort | Oladimeji Aladelokun |
| collection | DOAJ |
| description | Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remains unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing male and female immunodeficient Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome, and immunochemical analyses, and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism. Conversely, in male mice, asparagine treatment augments tumor growth, and is related to decreased numbers of macrophages, and a reduction in CYP19-mediated 17β-estradiol secretion . Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis. |
| format | Article |
| id | doaj-art-dfd28f4750f64b5ca27049c61eaf8a31 |
| institution | OA Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-dfd28f4750f64b5ca27049c61eaf8a312025-08-20T02:30:14ZengElsevierPharmacological Research1096-11862025-05-0121510773610.1016/j.phrs.2025.107736Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromataseOladimeji Aladelokun0Katherine Benitez1Yuying Wang2Abhishek Jain3Domenica Berardi4Georgio Maroun5Xinyi Shen6Jatin Roper7Joanna Gibson8Kaelyn Sumigray9Sajid A. Khan10Caroline H. Johnson11Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USADepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; Program in Translational Biomedicine, Yale University School of Medicine, New Haven, CT, USADepartment of Genetics, Yale School of Medicine, New Haven, CT, USADepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USADepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USADepartment of Molecular Biochemistry and Biophysics, Yale University, New Haven, CT, USADepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USADivision of Gastroenterology, Department of Medicine, Duke University School of Medicine, NC, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USADepartment of Genetics, Yale School of Medicine, New Haven, CT, USADivision of Surgical Oncology, Department of Surgery, Yale School of Medicine, New Haven, CT, USA; Corresponding authors.Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; Corresponding authors.Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remains unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing male and female immunodeficient Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome, and immunochemical analyses, and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism. Conversely, in male mice, asparagine treatment augments tumor growth, and is related to decreased numbers of macrophages, and a reduction in CYP19-mediated 17β-estradiol secretion . Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis.http://www.sciencedirect.com/science/article/pii/S1043661825001616Gastrointestinal cancer- colorectalAsparaginePre-clinical modelsEstrogen signalingSex differencesAromatase |
| spellingShingle | Oladimeji Aladelokun Katherine Benitez Yuying Wang Abhishek Jain Domenica Berardi Georgio Maroun Xinyi Shen Jatin Roper Joanna Gibson Kaelyn Sumigray Sajid A. Khan Caroline H. Johnson Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase Pharmacological Research Gastrointestinal cancer- colorectal Asparagine Pre-clinical models Estrogen signaling Sex differences Aromatase |
| title | Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase |
| title_full | Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase |
| title_fullStr | Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase |
| title_full_unstemmed | Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase |
| title_short | Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase |
| title_sort | sex specific effects of exogenous asparagine on colorectal tumor growth 17β estradiol levels and aromatase |
| topic | Gastrointestinal cancer- colorectal Asparagine Pre-clinical models Estrogen signaling Sex differences Aromatase |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825001616 |
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