Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis
Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in ca...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/59686 |
| _version_ | 1811168086613557248 |
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| author | Trayambak Pathak Maxime Gueguinou Vonn Walter Celine Delierneux Martin T Johnson Xuexin Zhang Ping Xin Ryan E Yoast Scott M Emrich Gregory S Yochum Israel Sekler Walter A Koltun Donald L Gill Nadine Hempel Mohamed Trebak |
| author_facet | Trayambak Pathak Maxime Gueguinou Vonn Walter Celine Delierneux Martin T Johnson Xuexin Zhang Ping Xin Ryan E Yoast Scott M Emrich Gregory S Yochum Israel Sekler Walter A Koltun Donald L Gill Nadine Hempel Mohamed Trebak |
| author_sort | Trayambak Pathak |
| collection | DOAJ |
| description | Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer. |
| first_indexed | 2024-04-10T16:20:09Z |
| format | Article |
| id | doaj.art-5281232761db416a876d72cbe79942a1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T16:20:09Z |
| publishDate | 2020-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5281232761db416a876d72cbe79942a12023-02-09T14:52:14ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.59686Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasisTrayambak Pathak0Maxime Gueguinou1Vonn Walter2https://orcid.org/0000-0001-6114-6714Celine Delierneux3Martin T Johnson4Xuexin Zhang5Ping Xin6Ryan E Yoast7Scott M Emrich8Gregory S Yochum9Israel Sekler10https://orcid.org/0000-0002-7550-1550Walter A Koltun11Donald L Gill12Nadine Hempel13Mohamed Trebak14https://orcid.org/0000-0001-6759-864XDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, United States; Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, United States; Penn State Cancer Institute. The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, United States; Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelDepartment of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States; Penn State Cancer Institute. The Pennsylvania State University College of Medicine, Hershey, United States; Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, United StatesDepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United StatesDespite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer.https://elifesciences.org/articles/59686calcium signalingmitochondrial calciummetastasisColorectal cancerHIF1a |
| spellingShingle | Trayambak Pathak Maxime Gueguinou Vonn Walter Celine Delierneux Martin T Johnson Xuexin Zhang Ping Xin Ryan E Yoast Scott M Emrich Gregory S Yochum Israel Sekler Walter A Koltun Donald L Gill Nadine Hempel Mohamed Trebak Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis eLife calcium signaling mitochondrial calcium metastasis Colorectal cancer HIF1a |
| title | Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis |
| title_full | Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis |
| title_fullStr | Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis |
| title_full_unstemmed | Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis |
| title_short | Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis |
| title_sort | dichotomous role of the human mitochondrial na ca2 li exchanger nclx in colorectal cancer growth and metastasis |
| topic | calcium signaling mitochondrial calcium metastasis Colorectal cancer HIF1a |
| url | https://elifesciences.org/articles/59686 |
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