Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth
Abstract Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblasto...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06442-x |
| _version_ | 1827381922672672768 |
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| author | Yong Zuo Jiawei Bai Huiyuan Bai Siyu Tian Hongtao Sun Zhenhua Shi Peng Yu Guofen Gao Yuan Li Yan-Zhong Chang |
| author_facet | Yong Zuo Jiawei Bai Huiyuan Bai Siyu Tian Hongtao Sun Zhenhua Shi Peng Yu Guofen Gao Yuan Li Yan-Zhong Chang |
| author_sort | Yong Zuo |
| collection | DOAJ |
| description | Abstract Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblastoma N2a (neuro-2a) cell proliferation and tumor growth in nude mice. Tmprss6 inhibits Smad1/5/8 phosphorylation by cleaving the bone morphogenetic protein (BMP) co-receptor, hemojuvelin (HJV). Ordinarily, phosphorylated Smad1/5/8 binds to Smad4 for nuclear translocation, which stimulates the expression of hepcidin, ultimately decreasing the export of iron through ferroportin 1 (FPN1). The decrease in cellular iron levels in neuro-2a cells with elevated Tmprss6 expression limited the availability of the metal forribo nucleotide reductase activity, thereby arresting the cell cycle prior to S phase. Interestingly, Smad4 promoted nuclear translocation of activating transcription factor 3 (ATF3) to activate the p38 mitogen-activated protein kinases signaling pathway by binding to ATF3, inducing apoptosis of neuro-2a cells and inhibiting tumor growth. Disruption of ATF3 expression significantly decreased apoptosis in Tmprss6 overexpressed neuro-2a cells. Our study describes a mechanism whereby Tmprss6 regulates the cell cycle and apoptosis. Thus, we propose Tmprss6 as a candidate target for inhibiting neuronal tumor growth. |
| first_indexed | 2024-03-08T14:11:57Z |
| format | Article |
| id | doaj.art-33a836c776714b259f3daa1fac00021e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T14:11:57Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-33a836c776714b259f3daa1fac00021e2024-01-14T12:38:17ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111110.1038/s41419-024-06442-xTransmembrane serine protease 6, a novel target for inhibition of neuronal tumor growthYong Zuo0Jiawei Bai1Huiyuan Bai2Siyu Tian3Hongtao Sun4Zhenhua Shi5Peng Yu6Guofen Gao7Yuan Li8Yan-Zhong Chang9Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityLaboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal UniversityAbstract Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblastoma N2a (neuro-2a) cell proliferation and tumor growth in nude mice. Tmprss6 inhibits Smad1/5/8 phosphorylation by cleaving the bone morphogenetic protein (BMP) co-receptor, hemojuvelin (HJV). Ordinarily, phosphorylated Smad1/5/8 binds to Smad4 for nuclear translocation, which stimulates the expression of hepcidin, ultimately decreasing the export of iron through ferroportin 1 (FPN1). The decrease in cellular iron levels in neuro-2a cells with elevated Tmprss6 expression limited the availability of the metal forribo nucleotide reductase activity, thereby arresting the cell cycle prior to S phase. Interestingly, Smad4 promoted nuclear translocation of activating transcription factor 3 (ATF3) to activate the p38 mitogen-activated protein kinases signaling pathway by binding to ATF3, inducing apoptosis of neuro-2a cells and inhibiting tumor growth. Disruption of ATF3 expression significantly decreased apoptosis in Tmprss6 overexpressed neuro-2a cells. Our study describes a mechanism whereby Tmprss6 regulates the cell cycle and apoptosis. Thus, we propose Tmprss6 as a candidate target for inhibiting neuronal tumor growth.https://doi.org/10.1038/s41419-024-06442-x |
| spellingShingle | Yong Zuo Jiawei Bai Huiyuan Bai Siyu Tian Hongtao Sun Zhenhua Shi Peng Yu Guofen Gao Yuan Li Yan-Zhong Chang Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth Cell Death and Disease |
| title | Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth |
| title_full | Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth |
| title_fullStr | Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth |
| title_full_unstemmed | Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth |
| title_short | Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth |
| title_sort | transmembrane serine protease 6 a novel target for inhibition of neuronal tumor growth |
| url | https://doi.org/10.1038/s41419-024-06442-x |
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