Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines
The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor governs a variety of biological processes, including metabolism, by acting on distinct molecular targets in different subcellular compartments. In the cytosol, inactive PTEN can be recruited to the plasma membrane...
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MDPI AG
2023-08-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/8/939 |
| _version_ | 1831516771997188096 |
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| author | Zoe N. Loh Mu-En Wang Changxin Wan John M. Asara Zhicheng Ji Ming Chen |
| author_facet | Zoe N. Loh Mu-En Wang Changxin Wan John M. Asara Zhicheng Ji Ming Chen |
| author_sort | Zoe N. Loh |
| collection | DOAJ |
| description | The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor governs a variety of biological processes, including metabolism, by acting on distinct molecular targets in different subcellular compartments. In the cytosol, inactive PTEN can be recruited to the plasma membrane where it dimerizes and functions as a lipid phosphatase to regulate metabolic processes mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the metabolic regulation of PTEN in the nucleus remains undefined. Here, using a gain-of-function approach to targeting PTEN to the plasma membrane and nucleus, we show that nuclear PTEN contributes to pyrimidine metabolism, in particular <i>de novo</i> thymidylate (dTMP) biosynthesis. PTEN appears to regulate dTMP biosynthesis through interaction with methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a key enzyme that generates 5,10-methylenetetrahydrofolate, a cofactor required for thymidylate synthase (TYMS) to catalyze deoxyuridylate (dUMP) into dTMP. Our findings reveal a nuclear function for PTEN in controlling dTMP biosynthesis and may also have implications for targeting nuclear-excluded PTEN prostate cancer cells with antifolate drugs. |
| first_indexed | 2024-03-10T23:44:38Z |
| format | Article |
| id | doaj.art-73d3efd7e56e4cd3884f58693e85acf3 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T23:44:38Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-73d3efd7e56e4cd3884f58693e85acf32023-11-19T02:09:09ZengMDPI AGMetabolites2218-19892023-08-0113893910.3390/metabo13080939Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell LinesZoe N. Loh0Mu-En Wang1Changxin Wan2John M. Asara3Zhicheng Ji4Ming Chen5Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pathology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USADivision of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USADepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USADepartment of Pathology, Duke University School of Medicine, Durham, NC 27710, USAThe phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor governs a variety of biological processes, including metabolism, by acting on distinct molecular targets in different subcellular compartments. In the cytosol, inactive PTEN can be recruited to the plasma membrane where it dimerizes and functions as a lipid phosphatase to regulate metabolic processes mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the metabolic regulation of PTEN in the nucleus remains undefined. Here, using a gain-of-function approach to targeting PTEN to the plasma membrane and nucleus, we show that nuclear PTEN contributes to pyrimidine metabolism, in particular <i>de novo</i> thymidylate (dTMP) biosynthesis. PTEN appears to regulate dTMP biosynthesis through interaction with methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a key enzyme that generates 5,10-methylenetetrahydrofolate, a cofactor required for thymidylate synthase (TYMS) to catalyze deoxyuridylate (dUMP) into dTMP. Our findings reveal a nuclear function for PTEN in controlling dTMP biosynthesis and may also have implications for targeting nuclear-excluded PTEN prostate cancer cells with antifolate drugs.https://www.mdpi.com/2218-1989/13/8/939nuclear PTENmetabolic compartmentalizationthymidylate biosynthesiscancer |
| spellingShingle | Zoe N. Loh Mu-En Wang Changxin Wan John M. Asara Zhicheng Ji Ming Chen Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines Metabolites nuclear PTEN metabolic compartmentalization thymidylate biosynthesis cancer |
| title | Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines |
| title_full | Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines |
| title_fullStr | Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines |
| title_full_unstemmed | Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines |
| title_short | Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines |
| title_sort | nuclear pten regulates thymidylate biosynthesis in human prostate cancer cell lines |
| topic | nuclear PTEN metabolic compartmentalization thymidylate biosynthesis cancer |
| url | https://www.mdpi.com/2218-1989/13/8/939 |
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