1. Biochemistry and Chemical Biology
  2. Cancer Biology
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Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia

  1. Xiaodong Zhang
  2. Alicia M Saarinen
  3. Taro Hitosugi
  4. Zhenghe Wang
  5. Liguo Wang
  6. Thai H Ho
  7. Jun Liu  Is a corresponding author
  1. Mayo Clinic, Arizona, United States
  2. Mayo Clinic, Minnesota, United States
  3. Case Western Reserve University, United States
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Cite this article as: eLife 2017;6:e31132 doi: 10.7554/eLife.31132

Abstract

Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during hypoxia remains poorly understood. Herein, we report that in various cancer cells upon oxygen deprivation, HIF-1 activation down-modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis. Proteomics and functional analyses identified hypoxia-inducible gene 2 (HIG2), a HIF-1 target, as a new inhibitor of ATGL. Knockout of HIG2 enhanced LD breakdown and fatty acid (FA) oxidation, leading to increased ROS production and apoptosis in hypoxic cancer cells as well as impaired growth of tumor xenografts. All of these effects were reversed by co-ablation of ATGL. Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in LDs away from the mitochondrial pathways for oxidation and ROS generation, thereby sustaining cancer cell survival in hypoxia.

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Author details

  1. Xiaodong Zhang

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Arizona, Scottsdale, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Alicia M Saarinen

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Arizona, Scottsdale, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Taro Hitosugi

    Department of Pharmacology, Mayo Clinic, Minnesota, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Zhenghe Wang

    Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Liguo Wang

    Division of Biomedical Statistics and Informatics, Mayo Clinic, Minnesota, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Thai H Ho

    Division of Hematology and Medical Oncology, Mayo Clinic, Arizona, Scottsdale, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Jun Liu

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Arizona, Scottsdale, United States
    For correspondence
    liu.jun@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3646-0004

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK089178)

  • Jun Liu

National Institute of Diabetes and Digestive and Kidney Diseases (DK109096)

  • Jun Liu

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

Ethics

Animal experimentation: This study used male athymic nude mice purchased from Taconic Biosciences. All of the animal experimental procedures were approved by the Mayo Clinic Institutional Animal Care and Use Committee. (IACUC Protocol A00001813-16).

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: August 9, 2017
  2. Accepted: December 2, 2017
  3. Accepted Manuscript published: December 19, 2017 (version 1)
  4. Version of Record published: December 21, 2017 (version 2)

Copyright

© 2017, Zhang 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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