Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia
| Autor: | Thai H. Ho, Liguo Wang, Taro Hitosugi, Xiaodong Zhang, Jun Liu, Zhenghe Wang, Alicia M. Saarinen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Mouse QH301-705.5 Science Lipolysis lipid droplet cancer metabolism Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Biochemistry and Chemical Biology Internal medicine Lipid droplet Neoplasms medicine Humans Biology (General) Beta oxidation fatty acid oxidation Cancer Biology reactive oxygen species General Immunology and Microbiology Catabolism hypoxia General Neuroscience Fatty Acids General Medicine Lipase Lipid Droplets Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Adaptation Physiological Cell biology Neoplasm Proteins 030104 developmental biology Endocrinology Apoptosis Cancer cell Adipose triglyceride lipase Medicine medicine.symptom Intracellular Research Article Human |
| Zdroj: | eLife eLife, Vol 6 (2017) |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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