Department 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 States
Celine Delierneux
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Martin T Johnson
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Xuexin Zhang
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Ping Xin
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Ryan E Yoast
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Scott M Emrich
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Gregory S Yochum
Department 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 States
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
Walter A Koltun
Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, United States
Donald L Gill
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, United States
Nadine Hempel
Department 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 States
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.
