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

doi:10.7554/ELIFE.59686

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

Department of Physiology and Cell Biology

Research output: Contribution to journal › Article › peer-review

37 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 language	English
Article number	e59686
Pages (from-to)	1-41
Number of pages	41
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/ELIFE.59686
State	Published - 1 Sep 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/ELIFE.59686

Cite this

Pathak, T., Gueguinou, M., Walter, V., Delierneux, C., Johnson, M. T., Zhang, X., Xin, P., Yoast, R. E., Emrich, S. M., Yochum, G. S., Sekler, I., Koltun, W. A., Gill, D. L., Hempel, N., & Trebak, M. (2020). Dichotomous role of the human mitochondrial na⁺ /ca2⁺ /li⁺ exchanger nclx in colorectal cancer growth and metastasis. eLife, 9, 1-41. Article e59686. https://doi.org/10.7554/ELIFE.59686

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

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.",

author = "Trayambak Pathak and Maxime Gueguinou and Vonn Walter and Celine Delierneux and Johnson, {Martin T.} and Xuexin Zhang and Ping Xin and Yoast, {Ryan E.} and Emrich, {Scott M.} and Yochum, {Gregory S.} and Israel Sekler and Koltun, {Walter A.} and Gill, {Donald L.} and Nadine Hempel and Mohamed Trebak",

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AU - Pathak, Trayambak

AU - Gueguinou, Maxime

AU - Walter, Vonn

AU - Delierneux, Celine

AU - Johnson, Martin T.

AU - Zhang, Xuexin

AU - Xin, Ping

AU - Yoast, Ryan E.

AU - Emrich, Scott M.

AU - Yochum, Gregory S.

AU - Sekler, Israel

AU - Koltun, Walter A.

AU - Gill, Donald L.

AU - Hempel, Nadine

AU - Trebak, Mohamed

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

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