Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia
- Mayo Clinic, Arizona, United States
- Mayo Clinic, Minnesota, United States
- Case Western Reserve University, United States
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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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).
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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Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia
eLife 6:e31132.
https://doi.org/10.7554/eLife.31132
