Dichotomous role of the human mitochondrial na+ /ca2+ /li+ exchanger nclx in colorectal cancer growth and metastasis

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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 HIF1a 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.

Original languageEnglish (US)
Article numbere59686
Pages (from-to)1-41
Number of pages41
JournaleLife
Volume9
DOIs
StatePublished - Sep 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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