| First Author | Pathak T | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32914752 | Mgi Jnum | J:355245 |
| Mgi Id | MGI:6477052 | Doi | 10.7554/eLife.59686 |
| Citation | Pathak T, et al. (2020) Dichotomous role of the human mitochondrial Na(+)/Ca2(+)/Li(+) exchanger NCLX in colorectal cancer growth and metastasis. Elife 9 |
| abstractText | Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca(2+) (mtCa(2+)) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa(2+) in tumorigenesis is highlighted by altered expression of proteins mediating mtCa(2+) uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na(+)/Ca(2+)/Li(+) exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa(2+) 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, mtCa(2+) overload leads to increased mitochondrial reactive oxygen species, which activate HIF1alpha signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa(2+) is a novel therapeutic approach in metastatic colorectal cancer. |
