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 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.

Data availability

No Large data sets have been generated from the current study.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files for all figures and supplementary figures have been provided as a submitted supplement.

Article and author information

Author details

  1. Trayambak Pathak

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Maxime Gueguinou

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Vonn Walter

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6114-6714
  4. Celine Delierneux

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Martin T Johnson

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xuexin Zhang

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ping Xin

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ryan E Yoast

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Scott M Emrich

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gregory S Yochum

    Biochemistry and Molecular Biology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Israel Sekler

    Physiology, Ben Gurion University, Ber Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7550-1550
  12. Walter A Koltun

    Department of Surgery, Division of Colon and Rectal Surgery, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Donald L Gill

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Nadine Hempel

    Pharmacology, Pennsylvania State University College of Medcicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Mohamed Trebak

    Cellular and Molecular Physiology, Pennsylvania State University College of Medcicine, Hershey, United States
    For correspondence
    mtrebak@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6759-864X

Funding

American Heart Association (9POST34380606)

  • Trayambak Pathak

National Heart, Lung, and Blood Institute (F30 HL147489)

  • Martin T Johnson

National Heart, Lung, and Blood Institute (R35-HL150778)

  • Mohamed Trebak

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol # 47350/Trebak, which was approved by the IACUC at the Penn State University college of medicine . Every effort was made to minimize animal suffering.

Human subjects: The Pennsylvania State University College of Medicine institutional review board approved this study. Approval under IRB Protocol number HY98-057EP-A. Prior to surgery, patients are consented to have resected tissues collected and banked into the Penn State Hershey Colorectal Disease Biobank. As outlined in the consent form and IRB protocol

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: June 4, 2020
  2. Accepted: September 7, 2020
  3. Accepted Manuscript published: September 11, 2020 (version 1)
  4. Accepted Manuscript updated: September 18, 2020 (version 2)
  5. Version of Record published: October 1, 2020 (version 3)

Copyright

© 2020, Pathak et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Trayambak Pathak
  2. Maxime Gueguinou
  3. Vonn Walter
  4. Celine Delierneux
  5. Martin T Johnson
  6. Xuexin Zhang
  7. Ping Xin
  8. Ryan E Yoast
  9. Scott M Emrich
  10. Gregory S Yochum
  11. Israel Sekler
  12. Walter A Koltun
  13. Donald L Gill
  14. Nadine Hempel
  15. Mohamed Trebak
(2020)
Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis
eLife 9:e59686.
https://doi.org/10.7554/eLife.59686

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