The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells
Abstract Background Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as me...
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| Language: | English |
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BMC
2025-07-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00405-2 |
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| author | Mohamed M. A. El Husseiny Roland Nilsson |
| author_facet | Mohamed M. A. El Husseiny Roland Nilsson |
| author_sort | Mohamed M. A. El Husseiny |
| collection | DOAJ |
| description | Abstract Background Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown. Methods Cancer cell lines were cultured with homocysteine in place of methionine, and growth responses were measured. Revertant cells capable of growing in homocysteine were generated through long-term culture with high B12 and analyzed using single-cell RNA-seq. Metabolite uptake/release was measured using isotope dilution and MTR activity was assessed using metabolic flux analysis (MFA). Functional rescue experiments were performed by overexpressing the B12-independent methionine synthase enzyme. Results We report evidence that methionine dependence is caused by low MTR activity secondary to a B12 deficiency. High levels of the B12 cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted “revertant” cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B12-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B12-dependent human enzyme had no effect. Conclusion Methionine dependence in cancer can be driven by low MTR activity secondary to B12 deficiency, at least in the cell lines studied. This mechanistic insight resolves a long-standing question in cancer metabolism and may open new avenues for exploiting the phenomenon for cancer therapy. |
| format | Article |
| id | doaj-art-6e7fa6e2e8884dd8a0e5b99a935c82da |
| institution | Kabale University |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-6e7fa6e2e8884dd8a0e5b99a935c82da2025-08-20T03:45:34ZengBMCCancer & Metabolism2049-30022025-07-0113111510.1186/s40170-025-00405-2The role of B12 deficiency and methionine synthase in methionine-dependent cancer cellsMohamed M. A. El Husseiny0Roland Nilsson1Cardiovascular Medicine Unit, Department of Medicine (Solna)Cardiovascular Medicine Unit, Department of Medicine (Solna)Abstract Background Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown. Methods Cancer cell lines were cultured with homocysteine in place of methionine, and growth responses were measured. Revertant cells capable of growing in homocysteine were generated through long-term culture with high B12 and analyzed using single-cell RNA-seq. Metabolite uptake/release was measured using isotope dilution and MTR activity was assessed using metabolic flux analysis (MFA). Functional rescue experiments were performed by overexpressing the B12-independent methionine synthase enzyme. Results We report evidence that methionine dependence is caused by low MTR activity secondary to a B12 deficiency. High levels of the B12 cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted “revertant” cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B12-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B12-dependent human enzyme had no effect. Conclusion Methionine dependence in cancer can be driven by low MTR activity secondary to B12 deficiency, at least in the cell lines studied. This mechanistic insight resolves a long-standing question in cancer metabolism and may open new avenues for exploiting the phenomenon for cancer therapy.https://doi.org/10.1186/s40170-025-00405-2One-carbon metabolismCobalaminMethylationCancer nutrition |
| spellingShingle | Mohamed M. A. El Husseiny Roland Nilsson The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells Cancer & Metabolism One-carbon metabolism Cobalamin Methylation Cancer nutrition |
| title | The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells |
| title_full | The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells |
| title_fullStr | The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells |
| title_full_unstemmed | The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells |
| title_short | The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells |
| title_sort | role of b12 deficiency and methionine synthase in methionine dependent cancer cells |
| topic | One-carbon metabolism Cobalamin Methylation Cancer nutrition |
| url | https://doi.org/10.1186/s40170-025-00405-2 |
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